Columbia  Mnihtv^itv 

mtijeCitpofi^etogorfe 

COLLEGE  OF  PHYSICIANS 

AND   SURGEONS 

^^ 

\>\    vM^Wiv^lJ^r^l 

^^^ 

Reference  Library 

Given  by 

Digitized  by  the  Internet  Archive 

in  2010  with  funding  from 

Open  Knowledge  Commons 


http://www.archive.org/details/diseasesofbonesOOIock 


CHAPTER  XVI 
DISEASES  OF  THE  BONES 

By  E.  a.  LOCKE 

Part      I. — Osteitis  Deformans 408 

Part     II. — Secondary  Hypertrophic  Osteoarthropathy       .      .431 

Part  III. — Ostitis  Fibrosa  Cystica 445 

Part    IV. — Osteopsathyrosis  (Osteogenesis  Imperfecta)      .      .  452 

Part     V. — Osteomalacia 462 

Part    VI. — Achondroplasia  (Chondrodystrophia  Foetalis)        .  475 
Part  VII. — Hereditary  Deforming  Chondrodysplasia  (Multi- 
ple Cartilaginous  Exostoses) 486 

Table  of  Contents 
Part  I 

OSTEITIS  DEFORMANS  (PAGET'S  DISEASE) 

Introduction 408 

Etiology 410 

Age 415 

Sex 415 

Pathology 415 

Chemical  Changes  in  the  Bones 419 

Metabolism  in  Osteitis  Deformans ' 420 

Symptoms 421 

X-ray  Examination 425 

"Mono-osteitic"  Form  (Schlesinger) 426 

Complications 426 

Course  and  Progress 427 

Diagnosis 428 

Treatment 430 

Bibliography  494 


Part  II 
SECONDARY  HYPERTROPHIC  OSTEOARTHROPATHY 

Introduction  ' 431 

Synonyms  431 


4o6  DISEASES  OF  THE  BONES 

Definition 431 

Historical 43i 

Relation  of  Club  Fingers  to  Secondary  Hypertrophic  Osteoarthropathy       .  432 

Eliology 433 

Morbid  Anatomy 43^ 

Symptoms 439 

Diagnosis 443 

Treatment 444 

Bibliography .      .      -      .  496 


Part  III 

OSTITIS  FIBROSA  CYSTICA 

Introduction 445 

Clinical  Types 445 

Etiology ; 44^ 

Pathology 447 

Symptoms  and  Course 449 

Diagnosis 450 

Treatment 45 1 

Bibliography 497 


Part  IV 

OSTEOPSATHYROSIS  (OSTEOGENESIS  IMPERFECTA) 

Introduction 452 

Types  of  Diseases 453 

Etiology 455 

Pathology 455 

Symptoms 457 

Fractures ■  45^ 

X-ray  Findings 458 

Metabolism 459 

Course  and  Prognosis 460 

Diagnosis 460 

Treatment 4^1 

Bibliography 498 


Part  V 

OSTEOMALACIA 

Introduction 4^2 

Clinical  Varieties 4^3 

Etiology 464 

Pathology 468 


CONTENTS  407 

Chemical  Composition  of  the  Bones 470 

Symptoms .   470 

Metabolism 472 

X-ray         473 

Course  and  Prognosis 473 

Diagnosis 473 

Treatment 474 

Bibliography  .      .      : 499 


Part  VI 

ACHONDROPLASIA  (CHONDRODYSTROPHIA  FOETALIS) 

Introduction 475 

Etiology 477 

Pathology 479 

General  Deformities 479 

Individual  Deformities 479 

Varieties 482 

Symptoms 483 

Course  and  Prognosis 485 

Diagnosis 485 

Treatment 485 

Bibliography 500 


Part  VII 

HEREDITARY  DEFORMING  CHONDRODYSPLASIA 

(MULTIPLE  CARTILAGINOUS  EXOSTOSES) 

Introduction 486 

Etiology 487 

Age     . 487 

Sex <      .  487 

Heredity 487 

Pathology 488 

Metabolism 491 

Symptoms  and  Clinical  Characteristics 49 1 

Complications 492 

Course  and  Prognosis 493 

Diagnosis 493 

Treatment 493 

Bibliography 501 


Part  I 
OSTEITIS  DEFORMANS  (FACET'S  DISEASE) 

Introduction 

Historical. — The  first  description  of  osteitis  deformans  was  given  by  Sir 
James  Paget^",  who  in  1876  presented  to  the  Medico-Chirurgical  Society 
of  London  a  paper  entitled  "On  a  Form  of  Chronic  Inflammation  of  Bones 
(Osteitis  Deformans)."  He  reported  five  cases  and  gave  a  masterly  descrip- 
tion of  the  clinical  picture,  symptoms  and  signs,  as  well  as  of  the  pathology 
of  the  disease.  So  complete  and  accurate  is  Paget's  account  of  the  disease 
that  comparatively  little  has  since  been  added  to  our  knowledge  of  the 
malady.  In  a  second  paper  published  in  1882  Paget^^  recorded  further 
observations  on  these  cases  and  reported  seven  additional  ones.  Thirteen 
years  after  his  first  communication  he  stated  in  a  short  report  that  he  had 
observed  a  total  of  twenty-three  cases. 

In  his  original  paper  Paget  describes  the  disease  as  follows :  "It  begins 
in  middle  age  or  later,  is  very  slow  in  progress,  may  continue  for  many  years 
without  influence  on  the  general  health,  and  may  give  no  other  trouble  than 
those  which  are  due  to  the  changes  of  shape,  size,  and  direction  of  the  dis- 
eased bones.  Even  when  the  skull  is  hugely  thickened,  and  all  its  bones 
exceedingly  altered  in  structure,  the  mind  remains  unaffected. 

"The  disease  affects  most  frequently  the  long  bones  of  the  lower  ex- 
tremities and  the  skull,  and  is  usually  symmetrical.  The  bones  enlarge  and 
soften,  and  those  bearing  weight  yield  and  become  unnaturally  curved  and 
misshapen.  The  spine,  whether  by  yielding  to  the  weight  of  the  overgrown 
skull,  or  by  change  in  its  own  structures,  may  sink  and  seem  to  shorten  with 
greatly  increased  dorsal  and  lumbar  curves ;  the  pelvis  may  become  wide ;  the 
necks  of  the  femora  may  become  nearly  horizontal,  but  the  limbs,  however 
misshapen,  remain  strong  and  fit  to  support  the  trunk. 

"In  its  earlier  periods,  and  sometimes  through  all  its  course,  the  disease 
is  attended  with  pains  in  the  affected  bones,  pains  widely  various  in  severity 
and  variously  described  as  rheumatic,  gouty,  or  neuralgic,  not  especially 
nocturnal  or  periodical.  It  is  not  attended  with  fever.  No  characteristic 
conditions  of  urine  or  faeces  have  been  found  in  it.  It  is  not  associated  with 
syphilis  or  any  other  known  constitutional  disease,  unless  it  be  cancer. 

"The  bones  examined  after  death  show  the  consequences  of  an  inflam- 
mation affecting,  in  the  skull  the  whole  thickness,  in  the  long  bones  chiefly 
the  compact  structure  of  their  walls,  and  not  only  the  walls  of  their  shafts 
but,  in  a  very  characteristic  manner,  those  of  their  articular  surfaces." 

408 


INTRODUCTION  '        409 

Medical  literature  previous  to  1876  contains  reports  of  cases  which  may- 
be examples  of  osteitis  deformans  but  the  description  of  the  condition  is  so 
meager  as  to  make  the  diagnosis  very  doubtful.  As  early  as  1801  Sau- 
cerotte^  described  the  case  of  a  man  who  died  at  forty  and  whose  bones 
generally  were  enlarged.  A  similar  instance  of  hypertrophy  of  nearly  the 
whole  skeleton  in  a  man  who  died  at  seventy  was  published  by  Rullier^^  in 
1809.  From  the  meager  description  given,  Paget  considers  these  cases  as 
doubtful.  Wrany'^^  in  1867,  recorded  a  case  of  a  woman  of  fifty  with 
"spongy  hypertrophy  of  the  cranium,  atrophy  of  the  face,  spongy  hyper- 
trophy of  the  spine,  pelvis  and  left  lower  leg  with  elongation."  He  sum- 
marizes the  process  as  a  "rarefying  osteitis  with  softening."  Paget  regarded 
this  case  as  probably  a  true  example  of  osteitis  deformans. 

The  only  undoubted  example  of  the  disease  described  prior  to  Paget 
was  published  by  Wilks''^  in  the  Transactions  of  the  Pathological  Society 
of  London  in  1869.  It  is  the  same  as  case  4  of  Paget's  series.  Czerny^,  in 
1873,  under  the  title  "Eine  lokale  Malacie  des  Unterschenkels"  records  a 
case  of  a  man  of  twenty- two  years  who  showed  local  softening  and  de- 
formity in  the  lower  tibia  and  fibula,  and  reviewed  six  other  similar  cases 
collected  from  the  literature.  The  disease  is  evidently  not  one  of  Paget's 
type  but  the  report  is  of  interest  as  Czerny  first  used  the  term  "osteitis 
deformans"  to  describe  the  condition. 

Synonyms. — A  considerable  array  of  formidable  names,  for  the  most 
part  in  accordance  with  the  author's  conception  of  the  pathology  of  the 
disease,  have  been  applied  to  this  condition.  A  list  of  the  most  common 
of  these  terms  is  as  follows :  osteitis  deformans  (Paget) ;  Paget's  disease ; 
osteomyelitis  fibrosa  (v.  Recklinghausen);  osteomalacic  locale  (D'Ollier); 
sclerose  osseuse  hypertrophique  (Menetrier  and  Gauckler) ;  osteomalacia 
chronica  deformans  hypertrophica  (Schmieden) ;  osteitis  ossifiante  diffuse 
(Lancereaux) ;  megalo-osteomyelitis  fibrosa  (Ganiciero) ;  osteolyose  (Lob- 
stein)  ;  spongiose  knockenhypertrophie  craniosclerosis  (Huschke) ;  osteo- 
malacie  hypertrophique  benigne  (Vincent) ;  hyperostose  generalisee,  osteite 
condensante  (Volkmann) ;  pseudo-rachitisme  senile  (Pozzi);  rhumatisme 
osteo-hypertrophique  des  diaphyses  et  des  os  plats  (Fereol) ;  diffuse  hyperos- 
tosis. The  disease  is  usually  and  most  appropriately  designated  as  osteitis 
deformans  or  Paget's  disease. 

Definition. — A  chronic  progressive  disease  of  the  skeleton  usually 
beginning  in  middle  life  which  leads  to  a  symmetrical  and  usually  painful 
thickening  and  bowing  of  the  long  bones  as  well  as  hypertrophy  and  defor- 
mity of  the  skull  and  other  units  of  the  skeleton. 

Incidence. — Osteitis  deformans  is  usually  classified  among  the  rare 
diseases  and  the  small  number  of  cases  reported  since  Paget's  first  publica- 
tion seems  to  bear  out  this  opinion.     Hurwitz^^  found  only   three   cases 


410  OSTEITIS  DEFORMANS 

among  over  30,000  medical  admissions  to  the  Johns  Hopkins  Hospital,  and 
DaCosta  the  same  number  in  38,000  admissions  to  the  Jefferson  Hospital, 
Philadelphia.  Higbee  and  Ellis^'^  found  158  cases  in  the  literature  to  1910. 
In  1914  DaCosta,  Funk,  Bergeim  and  Hawk^  collected  fifty  more  which 
had  been  subsequently  published  and  added  five  personal  observations 
making  in  all  213  cases  to  1914.  The  disease  is,  however,  by  no  means  so 
rare  as  these  facts  would  indicate.  The  subjective  symptoms  are  very 
seldom  prominent  or  severe  and  in  consequence  the  patient  very  seldom 
enters  a  hospital  and  in  my  experience  is  almost  invariably  found  in  the 
clinic  suffering  from  some  other  malady.  Furthermore,  in  a  majority  of 
cases  the  typical  changes  in  the  bones  are  revealed  by  X-ray  examination  of 
the  skeleton  when  not  otherwise  suspected.  During  the  past  twenty  years 
I  have  personally  studied  forty-eight  cases  and  have  probably  seen  as 
many  more.  With  the  exception  of  syphilis,  osteitis  deformans  is  the  most 
common  of  the  chronic  bone  diseases. 


Etiology 

The  cause  of  the  disease  is  unknown.  Numerous  theories  variously 
based  on  clinical,  histological,  chemical  and  bacteriological  characteristics 
of  the  disease  have  from  time  to  time  been  advanced  to  explain  the 
osseous  changes.  The  most  important  of  these  possible  etiologic  factors 
may  be  grouped  as  follows:  (i)  gout,  (2)  rheumatism,  (3)  bacterial  in- 
fection and  trauma,  (4)  malignant  disease,  (5)  disorders  of  the  endocrine 
glands,   (6)  syphilis,    (7)  trophic  nerves,   (8)  heredity,  (9)  arteriosclerosis. 

1.  Among  the  cases  in  England  the  presence  of  gout  has  been  so  com- 
mon as  to  suggest  some  significant  connection  with  osteitis  deformans  as 
an  etiologic  factor.  Paget  and  Hutchinson^^  especially  call  attention  to  the 
frequent  association  of  the  two.  The  fact  that  gout  is  so  prevalent  in 
England  and  that  the  disease  is  exceedingly  rare  in  association  with  osteitis 
as  observed  in  other  countries  would  seem  definitely  to  disprove  that  the 
disease  is  the  result  of  gout.  A  history  of  gout  was  obtained  but  once  in  my 
personal  series. 

2.  The  hypothesis  that  osteitis  deformans  is  to  be  regarded  as  due  to 
or  a  form  of  rheumatism  has  many  advocates  especially  among  the  French 
writers.  Huchard  and  Binet^^  were  thB  first  to  suggest  that  the  disease  is  of 
rheumatic  origin.  Lancereaux^^  and  Richard^^  attempted  to  prove  that 
osteitis  deformans  and  arthritis  deformans  are  very  closely  related  if  not 
identical.  A  close  study  of  the  published  cases  as  well  as  my  own  gives  no 
evidence  of  any  such  relationship  either  in  the  character  of  the  symptoms 
recorded  or  the  association  of  the  two  conditions. 


ETIOLOGY  411 

3.  Paget  in  his  original  article  concludes  that  the  disease  is  to  he 
regarded  as  an  inflammation  of  the  bones.  Hutchinson^^  is  of  the  opinion 
that  the  disease  "begins  in  consequence  of  contusion  of  one  bone  which 
spreads  by  infection  to  others."  A  few  cases,  but  too  few  to  carry  weight, 
have  been  reported  where  a  relationship  of  the  disease  to  an  antecedent 
injury  to  the  bone  is  suggested.  ChasteF  collected  fifty  cases  and  in  only 
twelve  was  there  any  history  of  trauma  however  remote.  He  admits  that 
trauma  may  localize  the  disease  as  in  tuberculosis  but  contends  that  it  is 
never  the  actual  but  only  a  possible  auxiliary  cause.  Previous  injury  was 
never  mentioned  in  any  of  my  cases.  Arcangeli^  claims  to  have  isolated 
an  organism  from  the  tibia  of  a  woman  with  osteitis  deformans  but  Ellis 
obtained  negative  results  in  two  cases  (quoted  by  DaCosta,  Funk,  Bergeim 
and  Hawk).  Critical  study  of  the  records  of  all  reported  cases  by  several 
authors  has  failed  to  furnish  any  justification  for  accepting  either  bacterial 
infection  or  trauma  as  causal  factors. 

4.  The  frequent  association  of  osteitis  deformans  and  malignant  tumors 
is  unquestioned.  In  1889  Paget^^  states  that  of  eight  cases  who  were  traced 
to  the  end  of  life  five  developed  either  cancer  or  sarcoma  and  on  the  basis  of 
this  experience  takes  the  stand  that  the  "intimate  relation  between  osteitis 
deformans  and  malignant  tumors  is  decisive."  Fourteen  of  my  series  have 
died  while  under  observation  and  three  have  shown  this  complication. 
Packard,  Steele  and  Kirkbride^^  found  cancer  in  four  and  one-half  per 
cent,  and  sarcoma  in  seven  and  one-half  per  cent,  of  all  cases  to  1901.  In 
all  probability,  as  suggested  by  Negellen*^,  the  irritation  resulting  from 
the  bony  lesions  in  osteitis  may  favor  the  development  of  a  neoplasm.  He 
regards  cancer  as  a  contemporary  disease  of  osteitis  in  the  aged  rather 
than  the  cause  of  it.  In  every  instance  it  has  occurred  late  in  the  course  of 
the  disease  of  the  bones. 

It  is  important  to  remember  that  osteitis  deformans  is  almost  invariably 
seen  at  the  time  of  life  when  the  incidence  of  malignant  disease  is  the 
greatest.  The  duration  of  malignant  disease  is  at  most  a  few  years  while  in 
the  case  of  osteitis  deformans  life  is  often  prolonged  twenty  or  even  thirty 
years  after  the  development  of  bone  deformity.  That  the  coexistence  of 
the  two  diseases  is  common  must  be  admitted  but  so  far  as  any  definite 
etiologic  relationship  between  the  processes  in  the  two  diseases  is  concerned 
we  have  no  evidence. 

5.  One  of  the  most  recent  and  plausible  theories  regarding  the  cause  of 
osteitis  deformans  is  that  the  bone  changes  result  from  some  disturbance  in 
the  function  of  certain  of  the  endocrine  glands.  That  perverted  function 
of  the  ductless  glands  may  lead  to  definite  and  marked  disorders  of  bone 
metabolism  has  been  repeatedly  proved.  Several  diseases  showing  charac- 
teristic bone  changes  are  known  to  be  due  to  such  causes  (acromegaly. 


412  OSTEITIS  DEFORMANS 

gigantism,  cretinism).  MacCallum  and  Voegtlin^  have  shown  experimen- 
tally the  influence  of  the  parathyroids  on  the  calcium  metabolism.  DaCosta, 
Funk,  Bergeim  and  Hawk^  found  marked  variations  from  the  normal  in 
the  calcium,  magnesium,  phosphorus  and  sulphur  metabolism  in  two  cases 
of  Paget's  disease.  The  very  nature  of  the  process  in  the  bones  in  osteitis  as 
well  as  the  general  course  of  the  disease  strongly  suggests  that  it  may  result 
from  such  perversion  of  glandular  function. 

On  the  other  hand,  pathological  studies  offer  but  little  support  for  such 
an  hypothesis.  Abnormalities  in  the  thyroid  are  recorded  in  but  seven  cases 
and  these  do  not  appear  suggestive;  sclerosis  (Levi^-  ",  Hudelo  and  Heitz^^, 
Higbee  and  Ellis^o),  atrophy  (Pescarolo  and  Bertolotti5^  Lyons^\  Gruner, 
Scrimger  and  Foster^'')  and  tumor  (Askanazy^).     The  thyroids  in  a  con- 
siderably greater  number  of  cases  were  found  normal.     The  adrenals  were 
reported  sclerotic  in  a  single  case  (Hudelo  and  Heitz22).     In  the  case  reported 
by  Bartlett^  the  hypophysis  "showed  a  ver>'  striking  preponderance  of  large 
polygonal    (chromophile)   cells  over  the  small  cuboidal  cells."     DaCosta, 
Funk,  Bergeim  and  Hawk^  noted  in  the  X-rays  a  "calcareous  deposit  in  the 
region  of  the  pineal  gland."    After  a  very  careful  discussion  of  the  subject 
Higbee  and  Ellis^o  conclude  that  "to  suggest  a  disturbance  in  the  internal 
secretions  as  a  possible  etiological  factor,  is  to  risk  the  accusation  of  adding 
without  sufficient  cause  to  an  already  overburdened  theory  of  the  disease." 
6.    One  of  the  earlier  views  is  that  osteitis  deformans  is  a  late  manifesta- 
tion of  hereditary  syphilis  (Lannelongue^^).     This  theory  has  called  forth 
wide  discussion  and  has  found  many  advocates  especially  among  the  French 
writers.     Lannelongue  based  his  theory  on  the  close  resemblance  of  the 
bone  changes  in  cases  of  Paget's  disease  and  those  occurring  in  late  syphilis 
as  well  as  certain  clinical  resemblances  in  the  symptoms  and  deformity  of  the 
legs.     Fournier^^  strongly  supports  this  theory.    On  the  basis  of  an  alleged 
identity  of  clinical  characteristics  in  the  osteopathies  of  infancy  and  child- 
hood resulting  from  hereditary  syphilis   and   osteitis  deformans,  he  con- 
cludes that  there  is  an  identity  of  origin.     Subsequent  studies,  however, 
by  a  large  number  of  authors  have  differentiated  the  two  conditions  both 
clinically  and  by  means  of  the  X-rays.    The  majority  of  cases  reported  have 
shown    no  evidence  whatsoever   of  the  presence  of  syphilis  nor  in  later 
years  has  the  Wassermann  test  given  positive  results.    Souques  and  Vallery- 
Radot^'^  in  191 3  published  the  results  of  a  careful  study  of  the  Wasser- 
mann reaction  in  osteitis  deformans.  'They  were  able  to  collect  further  cases 
in  which  the  tests  had  been  made  and  five  were  found  positive.     Weber''^ 
in   1908  showed  conclusively  that  congenital  syphilis  affecting  the  bones 
could   be   sharply   differentiated   from   osteitis   deformans   and    nearly   all 
writers  of  the  past  ten  years  hold  the  same  view.     None  of  my  series  of 
forty-eight  cases  gave  any  history  or  evidence  of  syphilis.    A  general  review 


ETIOLOGY  413 

of  all  reported  cases  also  shows  the  presence  of  antecedent  syphilis  to  be 
unusual.  Furthermore,  with  very  few  exceptions  many  observers  have  used 
mercury  and  iodides  in  osteitis  deformans  with  entirely  negative  results. 
Paget  himself  in  his  original  publication  mentions  that  he  found  no  evidence 
that  the  disease  was  related  to  syphilis.  ChasteF  in  1910  reviewed  the 
entire  question  of  etiology  and  discussed  exhaustively  the  evidence  for  and 
against  hereditosyphilitic  hypothesis.  He  concludes  that  the  syphilitic 
theory  is  "alluring  but  not  solid." 

7.  Several  authors  have  sought  to  show  that  osteitis  deformans  is  a 
distrophy  of  nervous  origin.  The  frequent  and  characteristic  changes  in 
the  bones  oqcurring  in  such  diseases  of  the  central  nervous  system  as  syringo- 
myelia and  tabes  have  suggested  by  analogy  that  the  bone  changes  in  this 
disease  may  also  be  of  a  trophic  nature  due  to  some  sort  of  nervous  lesion. 
Lancereaux^^  f^j-g^  suggested  that  the  nervous  system  may  play  a  part  in 
causing  osteitis  deformans.  Three  reported  cases  have  shown  sclerosis  of 
the  posterior  columns  of  the  cord  (Gilles  de  la  Tourette  and  Marinesco^^'  ^^»  ^^ 
two;  Levi^^,  one).  Slight  macroscopical  changes  in  the  posterior  columns 
were  observed  in  Pic's^^  case.  Stilling'^^  and  Lunn^''  report  minor  abnor- 
malities in  the  spinal  cord  which  do  not  seem  significant.  Further  evidence 
in  favor  of  this  view  is  believed  by  some  to  be  found  in  the  work  of  Schiff^^ 
who  produced  trophic  changes  in  the  tibiae,  fibulae  and  bones  of  the  feet  of 
dogs  by  section  of  the  sciatic  and  crural  nerves.  From  the  reported  results, 
however,  the  process  induced  seems  to  have  been  one  of  simple  atrophy 
(Schirmer).  A  chronic  myelitis  was  found  in  von  Recklinghausen's^^  case. 
Hudelo  and  Heitz^^  described  changes  in  the  spinal  cord  and  medulla  but 
which  they  did  not  regard  as  significant.  Prince^'^  in  1902  reviewed  the 
evidence  exhaustively  and  concludes  that  the  "lesions  found  in  the  spinal 
cord  and  peripheral  nerves  and  analogy  with  other  known  lesions  like  those 
of  tabes  and  syringomyelia  suggest  a  neuropathic  origin  similar  to  that  of 
the  myopathies." 

With  the  few  exceptions  cited  above  the  central  nervous  system  has 
always  been  found  normal  in  cases  of  osteitis  deformans.  The  lesions  de- 
scribed have  not  been  of  any  definite  type  and  in  several  instances  at  least 
it  seems  reasonable  to  attribute  them  to  arteriosclerosis.  Evidence  based 
on  such  irregular  and  unusual  findings  and  the  mere  analogy  to  certain 
diseases  of  the  central  nervous  system  with  bone  lesions  cannot  be  accepted 
as  of  much  weight.  Furthermore,  if  the  disease  were  of  neuropathic  origin 
it  would  appear  reasonable  to  expect  some  clinical  evidence  but  this  is 
entirely  wanting.  There  is,  therefore,  little  if  any  actual  support  for  this 
hypothesis. 

8.  The  part  which  heredity  plays  in  this  disease  is  somewhat  difificult  to 
determine.     Paget'^^  [^  iS8g  states  that  he  has  "tried  vainly  to  trace  any 


414  OSTEITIS  DEFORMANS 

hereditary  tendency"  in  his  twenty-three  cases.  Most  authors  are  inclined 
to  this  view.  Smith^^,  however,  believes  that  the  disease  belongs  to  the 
family  or  inherited  diseases.  DaCosta,  Funk,  Bergeim  and  Hawk^  collected 
213  typical  cases  of  osteitis  deformans  and  among  them  found  fifteen  in- 
stances with  positive  family  history,  or  seven  per  cent.  In  seven  there 
were  two  cases  in  the  same  generation,  and  in  seven  two  or  more  cases  in 
two  generations.  In  many  of  the  published  cases,  however,  no  mention  is 
made  of  family  history  and  in  all  probability  this  point  was  not  investigated 
in  a  majority. 

Evidence  of  the  existence  of  the  disease  in  the  same  or  previous  genera- 
tions was  carefully  sought  for  in  all  my  cases  with  the  result  that  in  ten  of  a 
total  forty-eight  (twenty  and  eight-tenths  per  cent.)  a  definite  positive  history 
was  obtained.  Five  cases  were  in  two  members  of  the  same  generation  and 
five  in  parent  and  child.  One  of  the  latter  group  gave  a  typical  history  of 
the  disease  in  both  his  father  and  paternal  grandfather.  Such  figures  can- 
not fail  of  significance  though  in  how  far  heredity  is  a  determining  factor  in 
causing  the  disease  cannot  be  stated.  Certain  it  seems  that  a  family  ten- 
dency in  osteitis  deformans  is  far  more  common  than  has  generally  been 
recognized  and  probably  lies  much  nearer  twenty  than  seven  per  cent. 

9.  The  atheromatous  theory  of  osteitis  deformans  has  received  much 
attention  throughout  the  literature  of  the  subject.  More  or  less  generalized 
arteriosclerosis,  usually  of  a  striking  type,  has  been  so  commonly  observed 
in  these  cases  that  it  may  almost  be  regarded  as  a  universal  manifestation  of 
the  disease.  The  interpretation  to  be  placed  on  this  association  is  difficult 
to  determine.  That  atheromatous  alterations  in  the  arteries  may  lead 
to  nutritive  changes  in  osseous  tissues  is  well  recognized  and  has  naturally 
led  to  the  supposition  that  the  association  of  arteriosclerosis  with  osteitis 
deformans  is  to  be  interpreted  as  the  cause  of  the  bone  changes  which  char- 
acterize the  disease.  Beclere^  suggests  that  the  bone  changes  are  due  to 
extreme  sclerosis  of  the  nutrient  arteries  of  the  affected  bones.  The  process 
in  the  bones  associated  with  such  vascular  changes  in  a  main  trunk  artery 
or  the  nutrient  vessel  are  as  a  rule  essentially  those  of  atrophy.  In  my  cases 
the  intensely  sclerosed  arteries  shown  in  the  X-rays  have  not  been  confined 
to  those  of  advanced  years  but  are  also  to  be  seen  in  many  of  those  observed 
in  early  middle  life. 

It  is  difficult  to  explain  why  if  osteitis  is  due  to  arteriosclerosis  the  disease 
does  not  occur  much  more  commonly  considering  the  great  frequency  of  the 
former  condition  at  the  period  of  life  when  osteitis  most  commonly  develops. 
L^yps  raises  the  question  if  both  the  sclerosis  and  the  process  in  the  bones 
may  not  be  due  to  some  dystrophy  of  unknown  cause. 

It  can  hardly  be  doubted  that  the  extreme  degree  of  atheroma  of  the 
vessels  so  constantly  met  with  must  play  some  role  etiologically  and  yet,  as 


PATHOLOGY  415 

Higbee  and  EUis^o  say,  "the  possibility  of  vascular  lesions   possessing  any 
specific  influence  in  producing  the  disease  appears  very  remote." 

Age 

Osteitis  deformans  is  spoken  of  as  a  disease  of  advanced  life  but  the 
figures  given  below  indicate  that  in  a  majority  of  cases  the  disease  begins 
before  the  fiftieth  and  rarely  as  early  as  the  thirtieth  year.  As  a  rule,  on 
the  other  hand,  the  patient  does  not  consult  a  physician  until  many  years 
later.  Packard,  Steele  and  Kirkbride'*^  from  a  study  of  sixty-seven  cases 
collected  from  the  literature,  give  the  average  age  at  onset  as  forty-nine  and 
a  half  years  and  the  average  age  when  first  coming  under  observation  as 
sixty-one.  The  forty-eight  cases  personally  observed  by  me  averaged  forty- 
five  and  a  half  years  at  time  of  onset  and  fifty-seven  at  time  of  coming  under 
observation.  In  only  eleven  instances  did  the  first  symptoms  appear  after 
fifty.  The  youngest  case  in  my  series  was  twenty-eight  and  the  oldest 
sixty-seven.  Several  instances  of  the  disease  at  ages  varying  from  twelve  to 
seventeen  years  are  often  quoted  but  a  careful  reading  of  the  original  re- 
ports has  convinced  me  that  none  are  genuine  cases  of  Paget 's  disease. 
Moizard  and  Bourges^^  report  one  instance  with  symptoms  first  noted  at 
twenty-one  which  seems  to  be  a  true  example  of  osteitis  deformans.  Still- 
ing^i  records  a  case  which  was  first  seen  at  age  ninety-two. 

Sex 

Males  are  probably  a  trifle  more  commonly  afiflicted.  Packard,  Steele 
and  Kirkbride^^  show  sixty-five  per  cent.,  my  series  fifty-eight  per  cent, 
males. 

Occupation  and  race  appear  to  play  no  part. 


Pathology 

The  pathology  of  this  disease  is  primarily  concerned  with  the  osseous 
system.  A  wide  variation  in  the  character  and  degree  of  the  bone  changes 
is  observed  depending  on  the  duration  and  extent  of  development  of 
the  process.  Of  whatever  stage,  however,  the  fundamental  changes  are 
unusually  definite  and  constant. 

The  bones  most  commonly  affected  are  those  which  give  to  the  disease  its 
peculiar  deformity,  namely,  the  skull  and  long  bones  of  the  legs  and  arms 
(Fig.  i).  The  great  majority  of  cases  show  the  first' changes  in  the  skull  and 
tibia,  which  seem  to  be  the  starting  point  of  general  skeletal  alterations. 


4i6  OSTEITIS  DEFORMANS 

Although  much  more  common  in  the  axial  bones  the  process  may  affect  any 
or  all  parts  of  the  skeleton.  A  few  examples  are  recorded  where  a  systematic 
X-ray  examination  of  the  entire  skeleton  has  shown  a  surprising  number 
of  bones  with  some  degree  of  alteration! 

The  disease  almost  invariably  shows  a  bilateral  but  very  asymmetrical 
and  irregular  involvement.  Klippel  and  WeiF^»  ^^  report  a  unique  exception. 
The  patient,  a  woman  of  fifty-six  years,  who  had  had  symptoms  for  eleven 
years  presented  typical  deformities  of  Paget's  disease  strictly  confined  to 
the  right  side  of  the  skeleton. 

The  gross  changes  (Fig.  i)  consist  primarily  in  a  general  thickening  and 
in  the  case  of  the  long  bones  of  a  conspicuous  bowing,  both  characteristics 
being  in  evidence  throughout  the  shaft  and  in  advanced  stages  involving  the 
epiphysis  as  well.  Not  infrequently  the  bone  is  increased  to  twice  its  normal 
size.  In  all  cases  the  bowing  is  in  the  nature  of  an  accentuation  of  the 
normal  curve  together  with  a  moderate  degree  of  torsion.  Actual  lengthen- 
ing also  takes  place.  The  normal  ridges  and  prominences  may  be  the  first 
to  show  the  hypertrophy.  As  the  disease  progresses  the  normal  markings 
of  the  bone  are  gradually  lost.  The  diseased  bone  appears  plump  and  mis- 
shapen and  has  been  likened  in  outer  appearance  to  roughly  hewn  stone. 
The  general  outline  is  fairly  regular  but  the  surface  is  extremely  uneven. 
Occasionally  the  even  outline  is  broken  by  rather  large  osteophytic  out- 
growths. Such  proliferation  in  a  few  instances  may  take  the  form  of  typical 
Heberden's  nodes.  These  outer  modifications  are  particularly  common  to 
the  tibia,  femur,  fibula,  humerus,  radius  and  ulna.  Paget^"  describes  the 
general  appearances  of  the  long  bones  as  follows : 

"The  outer  surface  of  the  walls  of  the  bones  was  irregularly  and  finely 
nodular,  as  with  external  deposits  or  outgrowths  of  bone,  deeply  grooved 
with  channels  for  the  larger  periosteal  blood-vessels,  finely  but  visibly  per- 
forated in  every  part  for  transmission  of  the  enlarged  small  vessels.  Every- 
thing seemed  to  indicate  a  greatly  increased  quantity  of  blood  in  the  vessels 
of  the  bone." 

The  periosteum  is  deeply  injected  in  many  places  and  moderately 
adherent.  On  section  the  diseased  bone  presents  a  picture  even  more 
varied  than  in  its  outer  aspects.  The  normal  appearance  is  completely 
altered  and  in  its  place  one  finds  an  irregular,  spongy,  coral-like  structure. 
In  places  the  hypertrophied  bony  tissue  is  soft,  very  rich  in  blood  and 
appears  as  very  coarsely  reticular  tissue.  Here  and  there  particularly  near 
the  outer  surface  of  the  shaft  are  areas  of  the  appearance  and  hardness  of 
ivory.  There  is  gross  evidence  of  increase  in  the  fat.  When  the  process  is 
advanced  the  medullary  cavity  is  entirely  obliterated  by  the  coarse,  irregu- 
lar, newly  formed  osteoid  tissue.  The  marrow  where  present  is  fibrous  or 
fatty  in  type. 


Fig.  I. — Osteitis  deformans;  calvarium  from  male,  age  63.  Note  the 
great  thickening,  porous  texture,  roughened  surface  and  deepening  of  the 
grooves  for  vessels. 


Facing  416 


PATHOLOGY  417 

Rarely  small  spaces  are  seen  in  the  shaft,  seldom  more  than  i  or  2  cm. 
in  diameter,  filled  with  reddish  gelatinous  material.  These  are  the  bone 
cysts  which  occur  with  such  a  variety  of  bone  diseases.  These  are  always 
small  in  size,  and  may  be  single  or  multiple. 

Butlin  (see  Paget^"),  who  made  the  pathological  studies  on  Paget's 
first  cases,  describes  minutely  the  microscopical  appearances.  The  Haver- 
sian systems  and  canals  were  much  diminished  in  number  but  enormously 
widened  and  many  were  confluent,  the  communicating  spaces  being  filled 
with  blood  vessels  and  ill  developed  tissue.  The  sides  of  these  canals  were 
not  smooth  but  eaten  out  to  form  the  so-called  Howship's  lacunae  so  charac- 
teristic of  inflammation.  New  and  incompletely  developed  bone  was  very 
evident  beneath  the  periosteum.  Fibrous  tissue  and  fibrocells  were  abun- 
dant. The  evident  absorption  of  the  original  bone  as  well  as  its  manner  of 
absorption  lead  Butlin  to  consider  the  process  as  a  true  chronic  inflamma- 
tion. 

Stilling^^  interprets  the  process  in  the  bones  as  a  rarefying  osteitis 
beginning  beneath  the  periosteum  and  gradually  involving  more  central 
portions  with  its  usual  accompaniment  of  new  bone  formation  which 
remains  uncalcified.  He  agrees  with  Butlin  in  his  interpretation  of  the 
process  as  essentially  an  inflammatory  one. 

Von  Recklinghausen's'^^  conception  is  that  the  first  changes  are  in  the 
nature  of  a  simple  osteomalacia  with  resulting  destruction  of  cortical  sub- 
stance of  the  bone  in  consequence  of  which  the  bone  bends.  Following  this 
there  is  an  inflammatory  process  in  the  malactic  areas  which  is  characterized 
by  a  transformation  of  the  fatty  and  lymph  marrow  into  fibrous  tissue  from 
which  a  network  of  compact  bone  develops  but  which  remains  uncalcified 
for  a  long  time. 

Since  these  early  papers  many  authors  have  discussed  the  changes  in 
the  bones  and  their  nature.  Very  little,  however,  has  been  added  to  these 
original  descriptions.  The  nature  of  the  process  is  now  accepted  as  a  double 
one,  namely,  first,  a  lacunar  absorption  of  bone  by  the  osteoclasts  (Askan- 
azy2),  and  second,  the  formation  of  new  "fibroosteoid"  tissue  which  may 
at  first  be  poor  in  lime  salts  and  late  in  the  disease  become  sclerotic.  In 
other  words,  there  is  a  double  process  of  rarefaction  (malacia)  and  new  bone 
formation  essentially  of  connective  tissue  origin.  There  seems  good  reason 
to  doubt  the  explanation  of  the  osseous  changes  as  a  true  inflammation. 

The  widespread  halisteresis  in  the  bones  possibly  explains  the  bowing  as 
well  as  the  tendency  to  spontaneous  fracture.  The  interpretation  of  the 
new  bone  formation  as  a  reparative  process  or  compensatory  effort  to 
strengthen  the  bone  which  has  yielded  to  the  strain  of  weight  bearing  or 
tension  from  muscle  action  seems  incorrect.  As  von  Recklinghausen  and 
others  have  said  the  parts  where  the  most  marked  proliferation  occurs  is  not 
Vol.  IV.  27 


4i8  OSTEITIS  DEFORMANS 

at  the  point  of  the  greatest  value  mechanically  and  is  out  of  all  proportion 
to  the  compensation  needed.  Furthermore,  the  same  alterations  take  place 
in  the  skull  and  other  bones  as  of  the  arms  where  the  above  named  mechani- 
cal factors  are  not  present.  While  it  is  impossible  to  deny  that  weight 
bearing  may  be  one  factor  in  causing  the  bowing  in  the  bones  of  the  legs  it 
cannot  be  the  chief  one  for  the  reasons  just  stated.  In  the  case  of  every 
afifected  bone  in  osteitis  deformans  the  bowing  is  strictly  in  the  nature  of 
an  accentuation  of  the  normal  curve.  The  most  natural  explanation  of  the 
characteristic  deformity  is  to  be  found  in  the  extreme  degree  of  general 
hypertrophy  present  in  the  bones  which,  because  of  the  tendency  to  actual 
increase  in  length,  induces  the  curve  since  the  more  or  less  fixed  ends  prevent 
any  considerable  longitudinal  growth. 

The  changes  in  the  skull  (Fig.  2)  are  among  the  earliest  and  most  striking 
observed  in  the  skeleton.  The  whole  calvarium  is  uniformly  enlarged  often 
to  an  extraordinary  degree.  In  several  cases  under  my  observation  the  skull 
increased  from  60  to  66  cm.  in  circumference  as  compared  with  a  normal  of 
54  to  58  cm.  One  of  Paget's  cases  measured  71  cm.  The  outer  surface  is 
fairly  regular  and  symmetrical  but  with  special  prominence  in  the  occipital, 
parietal  and  frontal  regions.  The  sutures  are  often  obscured.  Frequently 
the  mastoid  processes  of  the  temporal  bones  and  the  malar  bones  are  promi- 
nent. In  a  few  cases  the  bones  of  the  face  and  especially  the  lower  jaw  show 
considerable  hypertrophy  although  as  a  rule  these  bones  remain  unchanged. 
The  skull  cap  cuts  easily  due  to  its  soft  and  friable  nature.  All  normal 
structural  markings  may  be  absent.  As  in  the  case  of  the  long  bones  the 
tissue  is  rich  in  blood,  soft  and  augmented  in  thickness.  Islands  of  varying 
size  of  dense  homogeneous  bone  are  occasionally  present.  The  frontal 
sinuses  may  be  obstructed  or  entirely  obliterated  by  new  bone.  The  cal- 
varium in  a  case  reported  by  Pearce^^  measured  one  and  one-half  inches  in 
thickness  in  the  occipital  region.  The  inner  surface  is  more  irregular  and 
dense  than  the  outer  and  is  often  closely  adherent  to  the  dura.  The  grooves 
for  vessels  are  deep  and  the  orifices  voluminous. 

Marie,  Leri  and  Chatelin^*,  Leri  and  Chatelin3^  ^nd  Regnault^°  have  studied 
the  base  of  the  skull  in  Paget's  disease  and  find  very  constant  and  striking 
alterations.  They  observed  the  same  type  of  hypertrophy  and  deformity 
as  seen  in  other  parts  of  the  skeleton  and  affecting  all  structures.  As  a 
result  of  the  osseous  hypertrophy  there  is  a  varying  degree  of  narrowing  of 
all  foramina  which  give  passage  to  vessels  and  nerves  including  the  foramen 
ovale.  Leri  and  Chatelin  describe  a  "total  depression  of  the  skull  under  the 
weight  of  the  brain"  and  an  increase  in  the  transverse  and  anteroposterior 
diameter  of  the  cavity. 

The  spine  in  advanced  cases  is  markedly  changed.  It  is  rigid  through- 
out due  to  extensive  ankylosis  with  a  very  pronounced  kyphosis  involving 


Fig.  2. — Osteitis  deformans;  male,  age  63;  humerus,  femur,  clavicle,  tibia,  ulna  and 
radius.  Observe  the  enormous  thickening  throughout,  the  cylindrical  form,  the  spongy 
character,  roughened  surface  and  accentuation  of  the  normal  curves. 


Facing  418 


CHEMICAL  CHANGES  IN  BONES  419 

especially  the  dorsal  portion.  Scoliosis  of  slight  degree  is  likewise  described. 
The  bodies  of  the  vertebrae  appear  gross,  spongy  and  as  though  jammed 
together.  The  joint  structures  are  seldom  involved  except  late  in  the  course 
of  the  disease  when  limitation  of  motion  and  slight  pain  may  result  from 
the  deformity  at  the  articular  ends  of  the  bones.  Those  most  afTected  are 
the  knees,  hip,  ankle,  shoulder  and  elbow.  Actual  arthritis  has  been  reported 
but  probably  has  no  direct  connection  with  the  osteitis.  A  localized  perios- 
titis of  the  tibia  is  not  infrequent  and  usually  results  from  trauma. 

Cardiovascular  changes  of  an  outspoken  type  are  so  constantly  associated 
with  osteitis  deformans  that  they  should  be  regarded  not  as  a  complication 
but  as  an  essential  part  of  the  disease.  The  extreme  degree  of  atheroma  of 
the  arteries  met  with  in  this  disease  is  seldom  seen  except  with  syphilis  and 
occasionally  in  old  age.  So  marked  is  the  calcification  in  the  arteries  that 
in  many  of  the  cases  the  arteries  of  the  arms  and  legs  stand  out  in  the  X-rays 
as  dense  tortuous  shadows.  It  has  been  shown  that  there  is  relatively  more 
magnesium  in  the  arteries  than  in  the  bones  (DaCosta,  Funk,  Bergeim  and 
Hawk).  A  majority  of  the  cases  of  osteitis  deformans  toward  the  end  of 
life  develop  striking  clinical  evidences  of  arteriosclerosis  and  the  commonest 
causes  of  death  in  osteitis  are  apoplexy  and  cardiac  failure.  Mitral  and 
aortic  lesions  due  to  sclerosis  are  common  late  in  the  course  of  the  disease 
and  at  post-mortem  general  cardioarterial  sclerotic  changes  have  almost 
constantly  been  found. 

A  considerable  variety  of  lesions  particularly  of  the  spinal  cord  have 
been  described  and  are  mentioned  under  etiology.  As  no  distinct  type  of 
change  existed  in  the  autopsies  recorded  it  seems  safe  to  take  the  stand  that 
in  osteitis  deformans  there  is  no  constant  pathological  alteration  in  the 
central  nervous  system.  There  is  a  reasonable  basis  for  the  opinion  that  the 
miscellaneous  lesions  found  in  the  brain  and  cord  are  due  to  arteriosclerosis. 


Chemical  Changes  in  the  Bones 

Comparatively  few  chemical  analyses  of  the  bone  in  osteitis  have  been 
made.  The  results  are  variable  and  do  not  justify  any  very  definite  conclu- 
sions. Gilles  de  la  Tourette  and  Magdalaine^^  and  Robin*^^  found  a  slight  de- 
crease in  the  organic  matter  with  a  corresponding  slight  increase  in  the  total 
inorganic  constituents.  Precisely  the  reverse  of  these  results  were  shown  in 
the  analyses  of  Russell  (see  Paget^"),  Hudelo  and  Heitz,  Menetrier  and 
Gauckler^^  and  Moquot  and  Montier^^,  i.e.,  the  organic  matter  was  slightly 
above  and  the  inorganic  slightly  below  the  normal.  A  partial  explanation 
of  these  variations  is  to  be  found  in  the  probability  that  the  bones  analyzed 


420  OSTEITIS  DEFORMANS 

represented  different  stages  of  the  disease.   A  slight  diminution  in  the  content 
of  Hme  was  usually  f  Dund. 

Various  bones  from  four  of  my  cases  have  been  carefully  studied  chemi- 
cally with  much  more  constant  results.*  With  the  single  exception  of  a 
clavicle  every  bone  gave  an  increase  in  the  percentage  of  organic  matter, 
the  figures  ranging  from  42.60  to  48.54  per  cent.  Normal  bone  analyzed 
as  a  control  showed  an  organic  matter  content  of  37.83  per  cent.  The 
amount  of  fat  present  was  extremely  irregular  but  with  one  or  two  exceptions 
greatly  increased,  in  the  case  of  one  bone  reaching  12.05  P^r  cent.  Lime 
(CaO)  was  invariably  diminished.  One  bone  showed  41.80  per  cent,  of 
lime  while  the  remaining  seven  give  a  range  between  25.44  ^^^  28.15  per 
cent,  as  compared  with  the  normal  of  47.42  per  cent.  Magnesium  (MgO) 
was  less  changed  though  constantly  below  normal — minimum  0.14  per  cent., 
maximum  0.68  per  cent.,  normal  0.83  per  cent.  The  chlorine,  phosphorus 
and  sulphur  did  not  vary  significantly  from  the  normal. 


Metabolism  in  Osteitis  Deformans 

DaCosta,  Funk,  Bergeim  and  Hawk^  did  complete  metabolism  experi- 
ments on  two  cases  of  osteitis  deformans  and  have  given  an  exhaustive  dis- 
cussion of  the  subject.  In  these  experiments  there  was  marked  retention 
of  calcium  in  both  cases,  namely,  50.3  and  t8  per  cent.  Similar  studies  were 
made  on  two  of  my  cases  by  Dr.  Savage  and  a  retention  of  calcium  of  19.4 
and  II. 5  per  cent,  found.  McCrudden  (quoted  by  DaCosta,  Funk,  Bergeim 
and  Hawk)  found  6  per  cent,  recention  in  one  case.  Instead  of  the  normal 
urine-feces  calcium  excretion  ratio  of  i  4.5  to  i  :g  the  above  authors  obtained 
ratios  of  1:17  and  1:35.  The  ratios  in  my  cases  were  normal,  1:4.16  and 
1 18.35.  It  would  therefore  seem  that  the  "phenomenon  of  a  subnormal 
urinary  calcium  excretion"  in  osteitis  deformans  is  not  constant  in  all  cases. 
The  significance  of  calcium  retention  in  this  condition  is  not  altogether  clear. 
It  is  possible  that  further  metabolism  studies  may  show  a  variable  retention 
or  even  a  loss  depending  on  the  stage  of  the  disease.  At  least  a  partial  ex- 
planation of  this  retention  is  to  be  found  as  suggested  by  DaCosta,  Funk, 
Bergeim  and  Hawk  in  the  active  growth  of  fibroosteoid  tissue  which  is  so 
prominent  a  feajture  of  the  disease.  -While  the  available  analyses  seem  to 
indicate  that  as  a  rule  the  percentage  of  lime  in  osteitic  bones  is  low  it  is 
important  to  remember  that  the  bones  are  greatly  enlarged  indicating  that 
even  though  the  percentage  of  lime  salts  be  subnormal  the  total  content  may 

*The  analyses  were  made  by  Drs.  H.  Carleton  Smith  and  R.  L.  Emerson  of  the  Harvard 
Medical  School. 


SYMPTOMS  421 

be  normal  or  increased.  It  is  possible  also  that  the  enormous  degree  of 
calcification  of  the  arteries  may  account  for  some  of  the  retention  of  calcium. 

In  the  experiments  quoted  above  the  retention  of  magnesium  was  even 
greater  than  in  the  case  of  the  calcium,  i.e.,  35.1  and  58.7  per  cent.  My 
figures  for  magnesium  retention  were  19.9  and  10.9  per  cent,  and  McCrud- 
den's  20  per  cent.  As  in  the  case  of  the  calcium  the  normal  ratio  of  the  urine 
to  feces  excretion  of  magnesium  was  not  present.  In  both  cases  they  found 
the  amount  excreted  in  the  feces  greater  than  in  the  urine  which  is  the  re- 
verse of  the  normal.  In  one  of  my  cases  this  was  also  true  but  in  the  other 
the  magnesium  eliminated  by  the  kidneys  was  nearly  sixty  per  cent,  greater 
than  that  present  in  the  feces.  The  significance  of  the  magnesium  retention 
is  probably  the  same  as  that  of  the  calcium  according  to  these  authors. 

Phosphorus  likewise  showed  a  positive  balance,  being  respectively  28.6 
and  33.3  per  cent,  retention  in  their  two  cases.  The  proportion  eliminated 
by  the  kidneys  was  somewhat  below  normal.  This  retention  of  phosphorus 
is  interpreted  as  resulting  from  new  bone  formation.  In  contrast  to  the 
above  the  sulphur  loss  was  striking  in  one  case  while  in  the  other  it  was 
practically  normal. 

The  general  interpretation  of  the  results  of  the  above  metabolism  studies 
as  given  by  these  writers  seems  reasonable.  "May  it  not  be  possible  that 
in  advanced  osteitis  deformans  the  first  step  in  the  new  formation  of  bone 
or  osteoid  tissue  is  the  production  of  a  highly  sulphurized  organic  matrix, 
which  is  transformed  gradually  by  a  calcification  process  which  is  accompan- 
ied by  the  deposition  of  calcium,  magnesium  and  phosphorus  in  this  matrix? 
In  the  course  of  this  calcification  procedure  we  may  suppose  that  a  certain 
quota  of  the  sulphur  of  the  matrix  is  replaced  by  the  other  elements  men- 
tioned, a  process  which  must  entail  the  retention  of  calcium,  magnesium 
and  phosphorus  and  an  accompanying  increased  elimination  of  sulphur." 


Symptoms 

The  onset  is  invariably  insidious,  the  progress  of  the  disease  being  so 
gradual  that  the  patient  is  scarcely  ever  conscious  of  its  presence  until 
many  years  have  passed.  Very  commonly  his  first  knowledge  of  his  de- 
formity is  the  result  of  his  attention  being  drawn  to  it  by  his  friends  or 
family.  In  the  advanced  stages  of  the  disease  even,  the  patient  may  not 
have  observed  the  striking  changes  in  the  skeleton.  In  the  great  majority 
of  cases  the  first  symptom  is  pain,  usually  in  the  skin.  At  the  same  time  it 
may  be  discovered  for  the  first  time  that  the  leg  is  becoming  bowed.  Even 
when  the  deformity  is  marked  and  general  symptoms  have  developed  the 
condition  is  often  regarded  merely  as  the  infirmities  of  old  age.     Except  in 


422  OSTEITIS  DEFORMANS 

those  cases  suffering  from  pain  I  have  never  known  a  victim  of  the  disease 
to  seek  medical  advice  until  very  late  in  its  course.  In  hospital  practice 
the  disease  is  almost  invariably  discovered  in  a  patient  under  treatment  for 
some   entirely   independent   condition. 

Pain  is  usually  the  first  and  frequently  the  most  prominent  s>T:nptom  of 
the  disease.  It  is  most  commonly  located  in  the  lower  legs  and  especially 
over  the  front  of  one  or  both  tibiae  and  is  described  as  a  dull  "rheumatic" 
type  felt  deep  in  the  bones.  The  pain  is  seldom  constant  and  presents  all 
possible  grades  from  mere  discomfort  to  actual  paroxysms  of  a  lancinating 
character.  It  is  worse  at  the  end  of  the  day  or  at  night  and  especially  after 
long  standing  and  unusual  fatigue  as  in  walking.  The  patient  finds  it 
difficult  to  get  the  leg  in  a  comfortable  position.  A  prone  position  often 
affords  relief  suggesting  that  hyperemia  may  be  an  important  factor  in  caus- 
ing it.  Much  more  rarely  and  only  late  in  the  disease  the  same  type  of  pain 
may  be  felt  in  the  thighs,  pelvis,  spine  and  arms.  Pains  in  the  skull  are  rare. 
An  intense  burning  and  feeling  of  increased  local  temperature  often  accom- 
panies the  pain.  Elting^^  suggests  that  the  pain  is  possibly  the  result  of 
distention  of  the  periosteum.  Both  the  pain  and  burning  are  most  intense 
in  the  early  stages  of  the  disease  and  gradually  subside  after  a  varying  num- 
ber of  years.  A  few  cases  are  recorded  where  pain  was  absent  throughout 
the  course  of  the  disease  or  appeared  as  a  very  late  symptom.  Joncheray^'' 
differentiates  osteitis  into  the  painful  and  painless  forms,  the  latter  seldom 
seen  and  usually  in  women. 

Apart  from  pain,  symptoms  during  the  early  years  of  the  disease  are  not 
prominent.  Osteitis  is  often  seen  in  those  of  apparently  robust  health  and  it 
may  be  only  after  a  long  period  of  ten  to  fifteen  years  following  the  onset  of 
pain  that  the  patient  feels  any  limitations  from  the  process  in  the  bones. 
Sooner  or  later,  however,  in  a  majority  of  instances  the  patient  finds  that 
he  becomes  easily  fatigued  and  notes  a  stiffness  and  clumsiness  in  moving 
about.  Getting  up  from  a  sitting  or  prone  position  is  difficult.  Muscular 
weakness  is  likewise  common.  When  first  seen  the  patient  often  presents 
a  striking  picture  of  premature  senility.  In  the  late  stages  of  the  disease 
cardiovascular  symptoms  are  in  the  foreground  and  frequently  first  lead 
the  patient  to  seek  medical  advice.  Vertigo,  palpitation  and  dyspnea  are 
among  the  most  common  subjective  symptoms.  Actual  cardiac  decompen- 
sation with  edema  is  not  unusual.  Extreme  arteriosclerosis  of  the  peripheral 
vessels  is  almost  constantly  found  in  the  late  stages  of  the  disease. 

One  of  the  most  constant  and  severe  symptoms  is  cramps  in  the  muscles 
of  the  lower  legs.  Two-thirds  of  my  cases  have  given  such  a  history.  In 
all  but  one  the  cramps  were  in  the  calf  of  the  leg.  In  one  instance  the 
paroxysms  of  pain  were  so  great  as  to  strongly  suggest  angina  cruris.  They 
almost  invariably  appear  soon  after  the  patient  goes  to  bed. 


SYMPTOMS  423 

More  than  half  of  my  cases  gave  a  history  of  failing  vision  and  it  seems 
probable  that  changes  in  the  eyes  are  fairly  constant.  The  marked  altera- 
tions taking  place  in  the  base  of  the  skull  can  hardly  fail  to  produce  some 
ocular  lesions.  Changes  in  the  choroid  and  retina  have  been  described  by 
Vergne''^  and  Glaessner^*.  Paget^^  records  that  of  his  twenty-three  cases 
four  became  totally  blind,  one  had  choroiditis  and  three  had  retinal  hemor- 
rhages. Gradual  impairment  of  hearing  is  the  rule  and  total  deafness  often 
results.  Apart  from  the  influence  of  arteriosclerosis  the  cause  is  probably 
to  be  found  in  the  compression  of  the  labyrinth  by  the  hypertrophy  of  the 
base  of  the  skull  as  suggested  by  von  Kutscha^"^. 

No  characteristic  mental  impairment  takes  place  in  Paget's  disease,  the 
occasional  memory  weakness  and  confusion  observed  being  only  those  in- 
cident to  old  age.    Headache  and  vertigo  have  been  mentioned  in  a  few  cases. 

The  muscles  of  the  legs  or  arms  if  the  bone  is  affected  show  atrophy  and 
occasionally  edema.  Tenderness  to  pressure  over  the  muscles  may  be 
present.  The  skin  of  the  lower  legs  undergoes  marked  alterations.  It  is 
thin,  often  irregularly  and  deeply  pigmented  and  sometimes  with  ulcerations 
or  atrophic  changes  resembling  cicatrices.  Hudela  and  Heitz^^  report  one 
case  with  melanoderma.  In  those  cases  with  great  enlargement  of  the  cal- 
varium  the  hair  is  thin  or  more  often  wanting.  The  sensations  and  reflexes 
are  normal.  The  blood  and  the  excreta  present  no  characteristic  variations 
from  the  normal. 

Since  the  disease  is  essentially  confined  to  the  skeleton  it  is  natural  that 
the  objective  signs  should  be  the  most  prominent.  As  the  disease  progresses 
the  deformities  become  more  and  more  pronounced  and  in  its  most  advanced 
form  afford  an  extraordinary  picture  (Fig.  3). 

A  study  of  the  reported  cases  together  with  my  series  indicates  that  in 
all  probability  the  disease  begins  in  a  single  bone  and  from  this  as  a  focus 
the  disease  progresses  by  a  gradual  involvement  of  other  or  all  units  of  the 
skeleton.  In  two  instances  of  very  advanced  types  which  have  come  under 
my  observation  X-rays  have  shown  practically  the  entire  osseous  system 
involved,  the  majority  of  the  bones  of  the  hands  and  feet  alone  remaining 
normal.  The  bone  first  attacked  is  with  few  exceptions  the  tibia  or  skull. 
It  is  claimed  by  several  authors  that  the  skull  may  be  the  only  portion  of 
the  skeleton  affected  for  many  years  and  undoubtedly  in  a  few  cases  this 
is  true.  The  femur  may  be  the  starting  point  of  the  disease  and  in  one  case 
the  clavicle  was  for  some  years  the  only  bone  showing  changes.  Wherever 
it  begins  the  disease  is  characterized  by  a  slow  but  steady  progress  and  a 
tendency  to  an  uneven  bilateral  and  symmetrical  form.  One  case  is  on 
record  where  the  disease  was  strictly  confined  to  one-half  the  skeleton 
(Klippel  and  WeiP^).  A  crossed  type  of  involvement  is  also  occasionally 
observed.     In  the  order  of  frequency  the  bones  most  commonly  attacked 


424  OSTEITIS  DEFORMANS 

are  the  tibia,  skull,  femur,  fibula,  clavicle,  pelvis,  radius,  ulna  and  humerus. 

The  head  appears  enormous  (Fig.  3)  but  on  close  examination  the  enlarge- 
ment is  found  to  be  largely  if  not  wholly  confined  to  the  calvarium.  It  is  sym- 
metrical but  with  a  tendency  to  irregularities  of  the  surface.  Especial  hy- 
pertrophy of  the  supraorbital  portion  of  the  frontal  bone  and  the  malar  pro- 
cesses gives  to  the  skull  a  very  massive  appearance.  The  sutures  are  par- 
tially or  completely  obliterated.  The  head  looks  too  large  for  the  body.  The 
neck  is  short  and  the  head  seems  to  rest  directly  on  the  shoulders.  In  the 
most  developed  cases  the  enormous  head  is  thrown  forward  with  the  chin 
nearly  touching  the  sternum.  Motion  of  the  head  is  greatly  limited  and  the 
chin  can  be  only  slightly  raised  from  the  chest.  In  contrast  the  face  is  small. 
A  few  cases  are  on  record  in  which  the  bones  of  the  lower  jaw  were  moder- 
ately hypertrophied.  The  marked  broadening  of  the  frontal  portion  of  the 
skull  gives  to  the  face  a  distinct  triangular  outline  (Marie^^).  A  large  ma- 
jority of  the  males  give  a  definite  history  of  having  year  by  year  been  obliged 
to  increase  the  size  of  their  hats  and  not  a  few  have  found  it  necessary  to 
have  their  hats  made  to  order. 

The  trunk  in  comparison  with  the  head  and  prominent  limbs  often 
appears  small.  The  thorax  is  compressed  laterally  and  has  a  variable 
quadrilateral  shape.  Immense  increase  of  the  anteroposterior  diameter 
accompanies  the  decrease  in  the  lateral.  The  whole  thorax  is  rigid  and  in 
consequence  the  respiration  is  mainly  diaphragmatic  in  type.  Hypertrophy 
of  the  ribs  takes  place  only  late  in  the  course  of  the  disease.  The  clavicles 
are  among  the  bones  earliest  involved  and  are  greatly  thickened  and  mis- 
shapen. Less  constantly  the  scapulae  may  show  similar  changes.  These 
modifications  give  to  the  entire  shoulder  girdle  a  striking  prominence.  The 
whole  spine  becomes  bowed  with  the  most  marked  curve  in  the  dorsal 
portion  finally  developing  complete  rigidity.     Scoliosis  is  rare. 

The  bones  of  the  upper  extremities  seldom  show  very  noticeable  altera- 
tions. Most  commonly  the  forearm  is  curved  in  its  lower  half  due  to  bowing 
of  the  ulna,  the  convexity  being  outward  and  backward  when  the  hand  is  in 
the  position  of  supination.  Pronation  is  usually  complete  but  supination  is 
much  restricted.  Anterior  bowing  with  thickening  of  the  humerus  is  less 
frequent.  In  these  bones  the  X-ray  may  very  often  show  only  a  third  or  half 
of  the  shaft  involved.  Gross  outward  changes  in  the  bones  of  the  hand  are 
never  observed  but  roentgenograms  will  in  almost  every  well  marked  case 
give  evidence  of  the  process  in  one  or  more  of  the  carpals  or  metacarpals. 

As  a  result  of  the  anterior  curve  of  the  spine  and  the  flexion  of  the  trunk 
on  the  thighs  the  abdomen  is  greatly  contracted  from  above  downward. 
The  costal  border  of  the  thorax  may  actually  rest  on  the  crests  of  the  ilia. 
The  abdomen  is  small,  protruding  and  marked  transversely  at  the  level  of 
the  navel  by  a  deep  groove. 


Fig.   3. — Osteitis   deformans;    male,  age  60. 


Facing  424 


SYMPTOMS  425 

The  changes  in  the  pelvis  are  among  the  most  noticeable  in  the  entire 
body.  It  is  very  broad  and  massive  with  abnormal  flaring  of  the  iliac  crests. 
The  general  shape  conforms  more  or  less  to  the  female  type. 

The  earliest,  most  constant  and  with  few  exceptions  the  most  pronounced 
deformities  are  to  be  found  in  the  legs.  If  confined  to  the  tibia  and  fibula 
the  bowing  is  confined  to  the  lower  leg.  When,  as  so  often  happens,  the 
femur  is  also  affected  the  curve  embraces  the  entire  leg  from  the  hip  to  the 
ankle.  Its  type  is  always  the  same,  namely,  a  broad  curve  with  the  convexity 
chiefly  forward.  No  other  condition  except  rickets  in  children  ever  gives 
such  an  extreme  degree  of  curvature  of  the  legs.  So  great  may  the  bowing 
become  that  the  legs  are  crossed  and  walking  is  possible  only  by  a  curious, 
awkward  motion  of  extreme  torsion  of  the  body  and  tilting  of  the  pelvis 
with  each  step  in  order  that  the  advancing  leg  may  clear  the  other.  When 
lying  down  or  sitting  the  legs  are  often  crossed  like  a  pair  of  open  scissors. 

On  standing  the  knees  and  ankles  are  considerably  flexed  and  the  feet 
held  somewhat  apart  strongly  everted  and  one  in  advance  of  the  other. 
The  eversion  accentuates  the  bowing  to  such  an  extent  that  the  inner  con- 
dyles may  be  widely  separated.  The  lower  legs  present  a  most  distinct  and 
characteristic  deformity,  the  most  striking  feature  of  which  is  the  even, 
broad,  forward  and  slightly  outward  curve  from  the  knees  to  the  ankles. 
The  tibia  has  lost  all  its  normal  markings  and  is  cylindrical  in  shape.  Except 
for  small  irregularities  the  surface  is  generally  smooth.  It  is  in  this  portion 
of  the  body  that  the  skin  shows  the  marked  changes  mentioned  earher. 

The  deformities  above  mentioned  give  to  the  sufferer  from  osteitis  de- 
formans a  posture  which  is  peculiar  and  in  advanced  stages  extremely  gro- 
tesque. The  enormous  head  which  is  carried  forward  with  the  chin  nearly 
touching  the  sternum,  the  strong  kyphosis  of  the  spine,  the  deformed  thorax, 
the  flexion  at  the  hip,  knee  and  ankle  joints  produce  the  peculiar  appearance 
which  Paget  likened  to  that  of  an  anthropoid  ape.  The  gait  is  strangely 
labored,  slow  and  waddling. 

X-ray  Examination 

X-ray  examination  (Fig.  4)  is  of  the  utmost  importance  not  only  as  essen- 
tial in  showing  the  type  of  bone  changes  but  more  especially  because  it  is 
the  only  means  by  which  the  extent  to  which  the  skeleton  is  invaded  by  the 
disease  can  be  determined.  In  the  very  early  stages  of  the  process  in  a  given 
bone  only  the  proximal  portion  of  the  shaft  may  be  involved,  as  is  often  true 
of  the  ulna  or  humerus  and  rarely  of  the  tibia.  As  a  rule,  however,  the  roent- 
genogram reveals  a  diffuse  change  in  the  texture  of  the  entire  bone.  All 
normal  markings  are  generally  lost.  The  marrow  space  is  not  evident  after 
a  moderately  advanced  stage  of  the  process  is  reached.    The  bone  is  enlarged. 


426  OSTEITIS  DEFORMANS 

bowed  evenly  from  end  to  end,  and  the  outline  is  fairly  even  except  for  an 
extreme  variation  in  the  amount  of  lime  salts  near  the  periosteum.  Legros 
and  Leri^"*  describe  the  outline  of  the  bones  as  "soft,  dim  and  sometimes  wavy, 
the  peripheral  parts  somewhat  rarefied  in  places  and  hardly  apparent  in  the 
X-ray."  The  same  authors  mention  certain  appearances  of  a  "cotton  wool- 
like tangled  skein"  structure  as  found  only  in  osteitis  deformans.  Wollen- 
berg^^  considers  the  "streaked  and  flakey  transparency"  of  the  bones  in  the 
X-rays  as  particularly  characteristic  of  the  disease.  No  layer  of  new  sub- 
periosteal bone  is  ever  seen.  In  places  the  bone  is  feathery  or  mossy  in 
texture  while  in  other  parts,  especially  near  the  joint  ends,  one  sees  a  very 
coarse  irregular  trabecular  structure.  Here  and  there  are  small  areas  of 
dense  bone  and  rarely  a  small  area  without  lime  representing  bone  cysts. 
Now  and  then  the  affected  bone  is  more  dense  than  normal  throughout. 
The  irregular  double  process  of  rarefaction  and  ossification  shown  in  the 
roentgenograms  finds  its  interpretation  in  the  histological  changes  de- 
scribed under  pathology. 

"Mono-osteitic"  Form  (Schlesinger) 

A  considerable  number  of  cases  of  osteitis  deformans  in  which  the  disease 
process  is  confined  to  one  bone  have  been  reported  but  in  only  a  few  instances 
has  the  diagnosis  been  verified  by  post-mortem  or  X-ray  examination.  Com- 
monly the  deformity  is  found  in  only  one  lower  leg  but  X-ray  examination 
reveals  a  more  or  less  widespread  process  involving  many  units  of  the  skele- 
ton. It  is  probable  that  Paget's  disease  frequently  begins  in  a  single  bone 
and  gradually  extends  to  others.  The  characteristic  course  of  the  disease 
as  studied  in  a  large  series  of  cases  by  means  of  the  X-rays  has  convinced 
me  that  the  lesions  of  osteitis  deformans  are  seldom  if  ever  limited  to  one 
bone  for  more  than  a  comparatively  few  years.  When  life  is  sufficiently 
prolonged  this  localized  process  takes  on  a  generalized  form. 

Hurwitz^^  (1914)  collected  all  the  cases  of  this  limited  type  of  osteitis 
which  were  confirmed  by  anatomical  or  radiographic  examination  and  re- 
ported one  new  case,  making  a  total  of  six.  In  the  cases  of  Bowlby^  and 
Hurwitz^^  the  femur  was  the  bone  affected  while  in  those  of  Schmieden^^, 
Katholicky^^  and  Schlesinger^^  there  was  involvement  of  one  tibia. 


Complications 

Contrary  to  the  general  opinion  fractures  are  by  no  means  rare  and 
usually  result  from  trifling  causes.  Nine  of  my  cases  give  a  history  of  spon- 
taneous fracture,  four  of  these  on  two  different  occasions.    Lewald^^  reports 


Fig   4— Osteitis  deformans;    male,    age    63.     X-rays  of  fibula   tibia  and  femur.     Note  the  uneven 
surface,  enlargement,  exaggerated  curves  and  double  process  of  rarefaction  and  sclerosis. 

Facing  426 


COURSE  AND  PROGRESS  427 

six  of  his  fourteen  cases  as  having  spontaneous  fractures.  Auffret's^  case 
had  four  fractures.  Callous  formation  following  fracture  is  prompt  and  heal- 
ing normal. 

Localized  periostitis  following  trauma  and  nearly  always  of  the  tibia 
is  present  at  some  stage  of  the  disease  in  a  considerable  percentage  of  cases. 
A  slight  injury  to  the  shin  often  results  in  an  exquisitely  tender  and  painful 
area  which  persists  for  months.  Spontaneous  recovery  takes  place  after  a 
varying  period.  Joint  complications  of  the  type  of  true  arthritis  deformans  or 
infectious  arthritis  have  occurred  so  rarely  with  osteitis  deformans  that  there 
seems  no  reason  for  accepting  the  view  of  some  authors  that  the  two  condi- 
tions are  related.  Almost  constantly,  however,  the  patient  complains  of 
stififness  and  slight  pain  in  the  joints.  Objective  signs  are  excessively  rare. 
X-rays  commonly  show  a  slight  degree  of  osteoarthritis.  There  is  sufificient 
reason  for  regarding  the  subjective  symptoms  in  the  articulations  as  the 
result  either  of  general  senile  changes  or  rarely  of  a  true  osteoarthritis. 

The  occurrence  of  malignant  disease  especially  of  the  bones  with  osteitis 
deformans  has  repeatedly  been  emphasized.  It  is  always  a  terminal  compli- 
cation occurring  many  years  after  the  onset  of  the  osteitis.  Sarcoma  is 
considerably  more  common  than  cancer  and  primary  in  the  osseous  system 
far  more  frequently  than  as  metastasis  from  internal  organs. 

In  every  well  marked  case  of  this  disease  which  has  come  under  my  ob- 
servation noteworthy  lesions  of  the  cardiovascular  system  have  been 
present.  All  have  arteriosclerosis  and  many  a  very  extraordinary  degree  of 
atheroma.  Mitral  and  aortic  insufhciency  and  myocardial  disease  very  often 
appear  during  the  last  years  of  life.  Apoplexy  is  one  of  the  common  causes 
of  death. 

Bronchitis,  emphysema  and  pulmonary  tuberculosis  are  the  chief  pul- 
monary complications  but  are  not  so  frequently  present  as  would  be  expected 
considering  the  deformity  of  the  thorax. 


Course  and  Progress 

One  of  the  most  characteristic  features  of  the  disease  is  its  chronicity. 
With  very  few  exceptions  the  process  in  the  bones  is  steadily  progressive,  lead- 
ing to  greater  and  greater  deformity  with  the  result  that  the  victim  sooner 
or  later  becomes  in  the  strict  sense  a  cripple.  In  a  few  instances  where  the 
legs  have  been  crossed  and  the  muscular  wasting  was  extreme  the  patient 
has  for  many  years  been  confined  to  bed.  General  disability  usually  goes 
hand  in  hand  with  the  growth  of  the  deformity,  yet  it  would  appear  that 
the  osteitis  does  not  materially  shorten  life.  Indeed,  it  is  very  noticeable  in 
reviewing  the  statistics  of  the  disease  that  the  majority  live  to  old  age,  death 


428  OSTEITIS  DEFORMANS 

often  occurring  only  after  the  sixth  and  sometimes  the  seventh  decade. 
The  exact  duration  of  the  disease  is  difficult  to  determine  since  the  onset  is 
so  indefinite.    A  course  of  twenty  to  thirty  years  is  not  rare. 

An  occasional  exception  is  found  to  the  usual  progressive  course  of  the 
disease  when  the  process  after  a  period  of  years  seems  to  become  quiescent, 
the  subsequent  years  of  life  showing  no  evidence  of  increase  in  the  deformity. 
The  possibility  of  such  a  quiescent  stage  in  the  course  of  osteitis  has  been 
proved  in  several  of  my  cases  by  repeated  X-rays  of  the  skeleton  over  a 
period  of  many  years.  Very  rarely  the  disease  may  come  to  a  standstill  and 
then  after  some  years  again  become  active. 

The  osteitis  is  never  the  direct  cause  of  death.  Among  the  complications 
leading  to  a  fatal  termination  cardiovascular  disease  with  or  without  asso- 
ciated renal  trouble  is  undoubtedly  the  most  common.  Next  in  importance 
is  malignant  disease,  bone  sarcoma  being  the  most  conspicuous.  Less  com- 
mon terminal  affections  are  pneumonia,  emphysema  and  bronchitis,  pul- 
monary tuberculosis  and  apoplexy.  A  few  cases  have  died  without  evidence 
of  a  terminal  complication  and  it  has  seemed  reasonable  to  attribute  death 
to  a  fatal  cachexia. 

Diagnosis 

With  the  possible  exception  of  the  rare  case  of  osteitis  of  a  single  bone  or 
the  unusual  borderline  case  diagnosis  is  never  difficult.  The  age,  character- 
istic history,  typical  and  unique  type  of  deformities  and  the  constant  and 
peculiar  X-ray  appearances  described  above  combine  to  form  a  definite 
picture  which  can  hardly  be  confused  with  any  other  disease  of  the  skeleton. 

From  the  true  diffuse  hyperostosis  of  the  skull  (leontiasis  ossea)  osteitis 
is  readily  differentiated.  In  the  former  the  process  consists  in  an  enormous 
hypertrophy  of  the  entire  skull  and  especially  the  bones  of  the  face  without 
involvement  of  other  parts  of  the  skeleton.  The  disease  almost  always  be- 
gins in  late  childhood. 

Rickets  bears  no  resemblance  whatsoever  to  osteitis  except  in  the  bowing 
of  the  legs  seen  in  adults  as  a  result  of  the  disease  in  childhood.  It  is  a  disease 
of  growing  bones  in  early  life  and  is  concerned  especially  with  the  epiphyses 
and  cartilages.  In  general  the  changes  in  the  bones  in  the  two  conditions 
bear  no  resemblance.  Likewise,  the  X-ray  appearances  of  the  bones  in  the 
two  conditions  could  never  be  confuse'd. 

Acromegaly  often  shows  some  changes  in  the  long  bones  and  these  to- 
gether with  the  enlargement  of  the  skull  and  kyphosis  may  lead  to  confusion 
of  the  two  diseases.  The  process  in  the  two  conditions  is  entirely  different 
in  nature  as  well  as  in  location.  In  acrom.egaly  the  soft  parts  are  chiefly 
involved  and  the  enormous  enlargement  of  the  hands,  feet  and  face  is  never 


DIAGNOSIS  429 

present  in  Paget's  disease.  The  calvarium  remains  unaltered  and  the  long 
bones  show  none  of  the  characteristics  of  the  deformities  common  to  osteitis. 
The  essential  osseous  changes  are  found  in  the  small  bones  of  the  hands  and 
feet.     Pain  is  absent.    Acromegaly  develops  at  a  considerably  earlier  age. 

Osteoporosis  senilis  has  been  confused  with  Paget's  disease  but  without 
reason  as  there  is  not  even  a  superficial  similarity  in  the  two  conditions. 
Osteoporosis  in  the  aged  is  merely  "an  anatomical  condition  and  not  a  dis- 
ease" (Pic).  The  process  is  general  throughout  the  skeleton  and  is  essen- 
tially an  atrophy  of  the  bone  with  absorption  and  resulting  increase  in  its 
fragility.  No  thickening  or  deformity  of  the  long  bones  so  characteristic  of 
osteitis  deformans  occurs.     Pain  is  absent. 

Secondary  pulmonary  hypertrophic  osteoarthropathy  in  its  final  stage 
has  in  a  few  recorded  cases  shown  X-ray  appearances  in  the  long  bones  some- 
what suggestive  of  osteitis.  While  the  texture  of  the  bone  and  general 
enlargement  may  be  comparable,  there  is  no  bowing.  The  massive  hands  and 
feet  with  extreme  clubbing  of  the  fingers  and  toes  invariably  accompany  such 
bone  changes.  There  is  nothing  simulating  the  grotesque  deformities  of 
Paget's  disease.  The  presence  of  the  primary  disease  in  osteoarthropathy  is 
also  an  important  consideration. 

Osteomalacia  and  the  osteitis  of  Paget  are  both  constitutional  diseases 
affecting  the  long  bones  especially,  the  process  being  in  some  respects  the 
same.  As  emphasized  by  Lunn^°,  in  both  diseases  a  fatal  cachexia  may 
finally  result  and  the  same  complications  occur.  In  all  other  features  the  two 
diseases  are  quite  distinct.  Osteomalacia  occurs  chiefly  in  women  and  in 
the  third  and  fourth  decade.  The  lesions  are  most  pronounced  in  the  bones 
of  the  pelvis  and  are  more  strictly  symmetrical.  When  the  long  bones  are 
involved  the  regular  curves  of  osteitis  are  absent  and  instead  one  finds 
angular  curves  resulting  from  fractures.  Atrophy  of  the  bone  is  the  pre- 
dominating feature.  The  X-ray  appearances  are  entirely  distinct.  There 
are  no  cranial  lesions.    The  general  posture  is  unlike  that  of  osteitis. 

Cases  of  osteitis  fibrosa  osteoplastica  (von  Recklinghausen^^)  often  bear 
a  close  resemblance  to  Paget's  disease  inasmuch  as  the  deformities  may  be 
somewhat  similar.  The  disease  begins  much  earlier  in  life  in  von  Reckling- 
hausen's disease  and  the  skull  is  normal.  The  process  in  the  bones  in  both 
diseases  shows  widespread  absorption  of  lime  and  the  formation  of  new 
fibroosteoid  bone  but  the  pathological  picture  in  the  former  is  greatly 
modified  by  extensive  cyst  and  tumor  formation.  Spontaneous  fractures 
are  much  more  frequent.  Instead  of  the  regular  bowing  of  the  bones  seen 
in  osteitis  deformans,  the  deformities  are  characterized  by  angular  curves 
and  multiple  hyperostoses  and  the  bones  are  greatly  enlarged  by  tumors. 

Localized  syphilitic  hyperostosis  of  the  tibia  may  give  a  superficial  re- 
semblance to  osteitis  deformans  but  otherwise  the  distribution  and  general 


430  OSTEITIS  DEFORMANS 

character  of  the  lesions  in  the  t\vo  diseases  are  quite  distinct.  The  general 
objective  features  of  osteitis  deformans  are  never  present  in  syphilitic  affec- 
tions of  the  bones  and  the  X-rays  are  entirely  unlike. 


Treatment 

Little  can  be  claimed  for  the  various  methods  of  direct  treatment  which 
have  been  advocated.  Drugs  such  as  arsenic,  potassium  iodide  and  mercury 
are  valueless.  When  the  pain  is  severe  preparations  of  salicylic  acid,  bro- 
mides or  the  analgesics  so-called  may  be  used.  As  the  pain  is  usually  present 
for  many  years  opiates  should  never  be  given  lest  the  patient  acquire  the 
habit.    Local  applications  of  heat  often  diminish  the  pain  temporarily. 

Treatment  directed  to  the  improvement  of  the  general  nutrition,  rest, 
diet  and  tonics,  often  gives  fairly  satisfactory  results.  Hydrotherapy  and 
light  massage  will  sometimes  materially  improve  the  general  body  tone. 
Peckham^^  reports  favorable  results  following  the  use  of  the  actual  cautery 
over  the  seat  of  pain  and  counterirritation  to  the  lumbar  spine.  Orthopedic 
procedures  for  the  correction  of  the  deformities  are  useless. 

The  remarkable  healing  following  fracture  with  partial  correction  of 
deformity  has  suggested  osteotomy  as  a  reasonable  procedure.  Surgical 
intervention  of  this  type  has  been  performed  on  three  cases  (Schmieden^^, 
Wollenberg^^  and  Sonnenberg^^).  While  healing  has  been  prompt  and 
complete  the  small  results  in  the  lessening  of  the  deformity  do  not  seem  to 
justify  the  procedure. 


Part  II 
SECONDARY  HYPERTROPHIC  OSTEOARTHROPATHY 

Introduction 

Synonyms 

Clubbed  fingers;  Hippocratic  fingers;  osteoarthropathie  hypertro- 
phiante  pneumique  (Marie) ;  secundare  hyperplastisches  Otitis  (Arnold) ; 
osteoartropatia  ipertrofica  secondarie  (Massalongo) ;  toxigene  Osteo- 
periostitis Ossificans  (Sternberg) ;  hypertrophic  pulmonary  osteoarthrop- 
athy; Marie's  disease. 

Definition 

A  condition,  characterized  by  general  and  symmetrical  clubbing  of  the 
fingers  and  toes,  often  associated  with  hypertrophy  of  the  long  bones  of  the 
feet  and  hands  and  less  frequently  with  painful  enlargement  of  the  long  bones 
of  the  forearms  and  legs.  The  condition  is  secondary  to  some  chronic 
and  rarely  an  acute  disease,  most  commonly  of  the  lungs. 

Historical 

Simple  clubbing  of  the  fingers  is  mentioned  in  some  of  the  earliest  of 
medical  writings.  Hippocrates  particularly  described  the  condition  as  occur- 
ring with  advanced  phthisis  and  empyema  and  emphasized  the  importance  of 
these  changes  as  diagnostic  of  purulent  pleural  effusion.  Many  of  the 
authors  following  Hippocrates  recognized  the  condition  as  found  with  many 
chronic  diseases  of  the  heart  and  lungs  but  always  emphasized  its  importance 
as  most  frequently  occurring  with  phthisis.  In  the  nineteenth  century  the 
subject  received  much  attention  in  medical  literature  and  gradually  an 
accurate  knowledge  developed  as  to  the  exact  nature  of  the  changes  in  the 
fingers  and  their  significance.  No  alterations  other  than  those  in  the  fingers 
were  ever  mentioned  by  these  writers  until  1889  when  von  Bamberger'  first 
described  general  thickening  and  sclerosis  of  the  long  bones,  associated  with 
clubbing  of  the  fingers,  occurring  late  in  the  course  of  two  severe  cases  of 
bronchiectasis.  In  a  second  paper  published  in  1891  the  same  author^ 
discussed  at  length  the  nature  and  extent  of  these  bony  changes  and  their 
relation  to  various  diseases.  The  "ossifying  periostitis"  in  the  bones  of  the 
arms  and  legs  he  found  with  a  considerable  variety  of  diseases,  bronchiec- 
tasis, empyema,  phthisis  and  cardiac  diseases. 

431 


432  SECONDARY  OSTEOARTHROPATHY 

Almost  coincidently  Marie"  (1891)  published  a  very  full  and  accurate 
description  of  the  process  in  the  long  bones  and  fingers,  based  on  eight 
cases.  Marie  considered  the  condition  always  secondary  to  some  primary 
disease,  chiefly  of  the  lungs,  and  suggested  the  term  "osteoarthropathie 
hypertrophiante  pneumique."  Because  of  this  careful  description  the  name 
"Marie's  Disease"  has  been  frequently  applied  to  this  condition. 

In  more  recent  years  the  subject  has  been  widely  studied  and  a  volu- 
minous literature  has  accumulated.  Papers  byWalteis^°  (i896),Massalongo2^ 
(1897),  Thayer^s  (^397  and  1898),  Janeway^^  (1903).  Thompson^^  (1904), 
Wynn^^  (1904),  Ebstein^  (1906)  and  Alexander^  (1906)  are  to  be  especially 
noted.  The  last  mentioned  author  in  1906  collected  from  the  literature 
seventy-seven  typical  cases  of  unquestioned  secondary  hypertrophic  osteo- 
arthropathy. In  a  careful  search  of  the  literature  up  to  191 5  I  succeeded  in 
assembling  144  typical  cases^^. 


Relation  of  Club  Fingers  to  Secondary  Osteoarthropathy 

In  his  second  paper  von  Bamberger  discussed  the  possible  relationship  of 
these  two  conditions  and  suggested  that  the  former  may  be  simply  an  early 
stage  of  the  latter.  He  based  his  conclusions  on  the  fact  that  three  of  his 
cases,  which  ante-mortem  gave  no  evidence  of  changes  other  than  the 
clubbed  fingers,  at  autopsy  showed  periostitis  of  many  of  the  long  bones. 
The  opinions  of  subsequent  authors  vary  widely  on  this  point.  Many 
including  Marie^^,  Lefebvre^^,  Thompson3^  Landis^S  Wynn^S  Janeway", 
Lemercier-^  Rauzier^^,  Walters^",  Geraudi\  Rgynaud  and  Audibert^S 
Mobius",  VedeP^  Villard3^  Comby^  and  Teleky^*  regard  the  two  as  closely 
related  if  not  identical.  As  opposed  to  this  view  Rendu  and  Boulloche^, 
Genova^°,  Labrit^^,  Bezangon  and  de  Jong^  and  others  hold  that  there  is  a 
distinct  difference  between  the  two  and  that  they  should  be  regarded  as 
independent  conditions. 

The  evidence  is  entirely  in  favor  of  the  former  group  and  according  to 
Landis  may  be  summarized  as  follows:  (i)  both  conditions  are  found  asso- 
ciated with  the  same  group  of  primary  diseases;  (2)  the  type  of  clubbing  is 
the  same,  the  differences  described  being  merely  the  result  of  difference  in 
the  stage  of  the  process;  (3)  clubbing  of  the  fingers  invariably  occurs  in 
secondary  hypertrophic  osteoarthropathy;  (4)  many  cases  which  appear 
to  be  simple  clubbing  are  shown  by  X-ray  examination  to  possess  alterations 
in  the  long  bones  precisely  the  same  as  those  seen  in  secondar\'  h^-pertrophic 
osteoarthropathy.  In  a  series  of  thirty-nine  cases  of  seemingly  simple  club 
fingers  studied  by  me  twelve  were  found  by  X-ray  examination  to  have  some 
changes  in  the  long  bones  representing  various  stages  of  development.  Subse- 


ETIOLOGY 


433 


quently  Kessel^^  made  a  careful  X-ray  study  of  thirty-two  cases  of  pulmo- 
nary tuberculosis  of  the  second  and  third  stages  with  varying  degrees  of 
clubbing  of  the  fingers.  In  five  no  bony  changes  were  found.  Seventeen 
others  were  shown  to  have  a  layer  of  new  bone  beneath  the  periosteum  of 
one  or  more  of  the  phalanges  of  the  hands  and  feet.  The  remaining  ten 
cases  all  had  unmistakable  and  characteristic  enlargement  of  some  of  the 
long  bones.  The  above  evidence  proves  beyond  a  doubt  that  the  two  are 
but  difTerent  stages  of  the  same  disease  and  should  be  considered  as  such 
clinically. 

Etiology  of  Hypertrophic  Osteoarthropathy 

The  great  majority  of  cases  of  secondary  hypertrophic  osteoarthropathy 
are  clearly  secondary  but  a  sufficient  number  have  been  reported  as  without 
a  primary  disease  to  raise  the  question  whether  the  condition  may  not  arise 
independently  of  any  other  disease.  Most  writers  are  in  accord  that  the 
changes  in  the  long  bones  and  finger  ends  are  always  secondary.  The 
literature,  however,  contains  twenty-one  cases  reported  as  examples  of 
secondary  hypertrophic  osteoarthropathy  without  relation  to  any  ante- 
cedent disease.  These  cases  were  critically  studied  by  me  in  1 9 1 5 .  Five  were 
found  to  be  atypical  or  so  doubtful  as  to  be  fairly  excluded  as  true  cases  of 
osteoarthropathy  (Gerhardt^^,  Gessler^^,  Postmantir^^,  Guerin  and  Etienne^'*, 
Schmidt^^).  In  three  others  a  definite  disease  is  mentioned  as  present 
which  is  among  those  known  to  cause  the  type  of  secondary  changes  in  the 
bones  under  discussion  and  which  it  seems  fair  to  consider  as  the  primary 
condition.  The  history  in  eight  others  strongly  suggests  the  presence  of  one 
of  the  group  of  primary  diseases  known  to  produce  osteoarthropathy  and  it 
therefore  appears  reasonable  to  challenge  them  as  cases  of  a  primary  type.  In 
none  of  the  remaining  five  cases  was  there  any  history  of  a  primary  disease 
and  in  each  instance  the  author  expressly  states  that  there  was  none.  Occur- 
ring as  it  does  with  such  a  variety  of  diseases  it  is  to  be  expected  that  in  some 
instances  the  evidence  of  the  primary  condition  should  be  difficult  to  find 
or  wanting.  Some  obscure  cardiac  or  pulmonary  condition,  some  focus  of 
infection,  syphilis  or  liver  cirrhosis  might  conceivably  exist  without  being 
manifest.  No  post-mortem  examination  was  made  in  any  of  these  five 
cases  and  without  such  a  final  test  it  would  seem  to  me  impossible  to  exclude 
the  possibility  of  a  primary  disease.  We  know  that  in  the  overwhelming 
majority  of  cases  Marie's  disease  is  characteristically  a  secondary  condition, 
and  are  justified,  therefore,  in  demanding  complete  proof  that  any  given  ex- 
ample is  primary.  The  five  cases  above  mentioned  while  seemingly  not 
secondary  to  any  other  disease  can  be  regarded  as  only  suggestive  of  the 
possibility  of  a  primary  form  of  hypertrophic  osteoarthropathy.  Until 
Vol.  IV.  28 


434  SECONDARY  OSTEOARTHROPATHY 

positive  evidence  is  forthcoming  that  such  a  primary  type  does  exist  we  may 
assume  that  the  condition  is  always  secondary. 

The  most  satisfactory  grouping  of  the  causative  diseases  was  published 
by  Teleky^  in  1897  and  is  as  follows: 

1.  Diseases  characterized  by  purulent  or  gangrenous  process,  pul- 
monary tuberculosis,  bronchiectasis,  empyema,  pyelonephritis,  dysentery. 

2.  Infectious  diseases  and  chronic  intoxications,  pneumonia,  pleuritis, 
influenza,  syphilis,  chronic  jaundice,  chronic  alcoholism. 

3.  Cardiac  disease,  especially  the  congenital  forms. 

4.  Malignant  tumors,  especially  of  the  lungs. 

In  1 91 5  I  collected  from  the  literature  139  typical  cases  to  which  were 
added  five  new  observations,  making  a  total  of  144.  The  primary  diseases 
in  these  cases  were  grouped  as  follows: 

1.  Diseases  of  the  respiratory  tract 112 

2.  Diseases  of  the  circulatory  tract 6 

3.  Diseases  of  the  alimentary  tract *.    .    .  13 

4.  Miscellaneous  diseases 7 

5.  Antecedent  disease  unknown 6 


144 


Nearly  half  of  the  above  group  of  144  reported  cases  followed  either 
bronchiectasis  or  pulmonary  tuberculosis.  The  most  common  causes  as 
shown  in  this  series  of  144  cases  and  arranged  in  order  of  frequency  are 
bronchiectasis,  pulmonary  tuberculosis,  empyema,  malignant  disease  of 
lungs  and  mediastinum,  valvular  heart  disease,  congenital  heart  disease, 
biliary  cirrhosis,  chronic  jaundice  and  chronic  enteritis.  The  above  grouping 
of  primary  diseases  is  unquestionably  very  inaccurate  as  many  of  the  pub- 
lished cases  are  not  fully  and  accurately  described.  The  recent  work  of 
Kessel^^  on  the  relation  of  hypertrophic  osteoarthropathy  to  pulmonary 
tuberculosis  emphasizes  the  importance  of  the  latter  disease  as  a  cause  of 
the  former.  There  is  good  evid&nce  for  the  assumption  that  osteoarthrop- 
athy is  more  frequently  associated  with  pulmonary  tuberculosis  than  any 
other  disease. 

The  actual  cause  of  the  process  occurring  with  such  a  wide  variety  of 
diseases  has  not  been  positively  determined.  The  multiplicity  of  antecedent 
diseases  makes  it  difficult  to  assume  -any  single  factor  present  in  all  which 
can  lead  to  the  characteristic  secondary  alterations  in  the  skeleton.  Several 
theories  have  been  advanced  to  explain  the  changes  found  in  the  osseous 
and  soft  tissues.  Von  Bamberger  suggested  the  theory  that  the  drumstick  fin- 
gers and  proliferative  periostitis  are  the  result  of  toxic  absorption,  that  is,  are 
due  to  some  chemical  action.     In  support  of  the  theory  of  toxic  origin 


ETIOLOGY  435 

von  Bamberger  argues  that  clubbing  of  the  fingers  is  never  seen  with  simple 
catarrhal  processes  in  the  lungs  and  in  phthisis  only  in  the  advanced  stages 
when  purulent  expectoration  is  present.  He  quotes  the  work  of  Wegner  who 
showed  experimentally  that  small  doses  of  phosphorus  developed  a  formative 
stimulation  on  cartilage  and  periosteum.  Similar  results  were  obtained  by 
Gils  in  animals  fed  with  arsenic.  Von  Bamberger  attempted  to  produce  the 
lesions  of  osteoarthropathy  in  rabbits  by  injecting  bronchiectatic  sputum 
into  the  rectum  but  his  results  were  negative.  Marie  strongly  advocates  the 
toxic  theory.  He  believes  that  the  lesions  are  the  "result  of  the  production  of 
putrid  or  fermented  substances  due  to  microorganisms  which  are  absorbed 
into  the  circulation  and  through  selective  action  exert  an  influence  on  certain 
parts  of  the  bones  and  joints."  It  is  evident  from  the  fact  that  this  disease 
occurs  with  certain  heart  lesions  and  other  conditions  where  no  form  of 
suppuration  exists  that  the  toxic  theory  alone  will  not  fit  all  cases.  Von  Bam- 
berger argues  that  the  greater  part  of  the  heart  cases  recorded  with  clubbing 
of  the  fingers  and  periosteal  changes  also  have  lung  complications.  He,  how- 
ever, admits  that  true  stasis  may  stimulate  proliferation  of  bone  and  that  in 
some  of  the  cardiac  cases  such  as  those  of  the  congenital  type  the  stasis  alone 
may  lead  to  the  alterations  in  the  end  phalanges  and  long  bones.  There 
seems  but  little  doubt  that  in  rare  cases  prolonged  venous  congestion  can 
produce  the  typical  changes  under  discussion  and  even  in  those  clearly  due 
to  toxic  agents  peripheral  stasis  may  also  be  a  factor.  There  is  some  evidence 
for  the  assumption  that  the  action  of  toxic  substances  in  the  circulation 
predisposes  the  bones  and  joints  to  the  alterations  known  to  occur  with 
congestion.  In  a  very  large  proportion  of  cases,  occurring  with  primary 
diseases  of  a  septic  type,  there  is  deep  cyanosis  especially  of  the  extremities 
and  this  peripheral  hyperemia  may  be  a  factor  of  prime  importance.  The 
rare  cases  occurring  with  hepatic  cirrhosis  and  malignant  tumors  may  be 
explained  on  the  basis  of  a  true  toxemia  though  not  of  bacterial  origin  and 
possibly  here  also  stasis  in  the  peripheral  circulation  plays  a  more  or  less 
important  part.  In  either  case  the  parts  most  afi^ected  are  the  distal  portions 
of  the  extremities,  namely,  those  parts  most  affected  in  osteoarthropathy. 
Thorburn^'^  (1893)  suggests  a  close  analogy  between  the  bone  and  joint 
changes  in  chronic  tuberculosis  and  osteoarthropathy  and  on  this  analogy 
bases  his  theory  of  a  tuberculous  origin  of  the  disease.  He  regards  the 
process  as  an  attenuated  tuberculosis  of  the  bones  and  joints.  Alamartine^^ 
in  1907,  published  a  very  comprehensive  paper  on  the  subject  and  finds  much 
evidence  for  the  tuberculosis  theory.  He  concludes  that  the  condition  is 
secondary  to  a  tuberculous  infection  and  considers  the  pathological  changes 
to  be  of  the  nature  of  a  subacute  infectious  osteoarthritis.  There  appears 
to  be  no  rational  basis  for  such  an  hypothesis,  however,  either  in  the  sug- 
gested analogy  or  in  a  close  study  of  the  reported  cases.     Clubbing  of  the 


436  SECONDARY  OSTEOARTHROPATHY 

fingers  is  commonly  associated  with  the  late  stages  of  chronic  pulmonary 
tuberculosis  but  in  every  such  case  one  must  admit  the  presence  of  foci  of 
toxemia  and,  in  a  majority  if  not  in  all,  cyanosis  is  also  present. 

Massalongo^s  believes  that  hypertrophic  pulmonary  osteoarthropathy  is 
not  entirely  dependent  on  diseases  of  the  respiratory  tract  or  on  circulatory 
disturbances  but  is  "the  consequence  of  causes  acting  contemporaneously  or 
alone,  among  which  the  arthritic  diathesis  plays  the  principle  role"  (Thayer^^). 
After  an  examination  of  the  cases  on  record  it  is  difficult  to  find  any  basis 
for  such  an  assumption. 

The  clubbing  of  the  fingers  occasionally  seen  in  certain  nervous  diseases 
as  well  as  certain  clinical  manifestations  common  to  those  and  to  osteo- 
arthropathy has  suggested  a  possible  relationship  between  osteoarthropathy 
and  diseases  of  the  nervous  system.  Several  authors  have  written  in  favor 
of  such  an  etiologic  relationship.  None  of  the  cases  cited,  however,  have 
shown  any  lesions  of  the  central  nervous  system.  Alexander^,  after  a 
critical  study  of  all  the  reported  cases,  concludes  that  there  is  no  evidence 
in  favor  of  the  nervous  origin  of  osteoarthropathy. 

Godlee^^  regards  osteoarthropathy  as  due  to  syphilis  but  later  writers 
have  been  unable  to  find  sufficient  evidence  for  such  a  claim.  In  a  careful 
search  of  the  literature  I  have  found  but  six  cases  of  the  condition  occurring 
with  syphilis.  One  was  associated  with  bronchiectasis,  one  with  chronic 
bronchitis  and  emphysema,  one  with  empyema  and  abscess  of  the  liver,  two 
with  pulmonary  tuberculosis  and  abscess  elsewhere  and  one  of  the  congenital 
type  with  jaundice. 

In  conclusion  at  least  two  principle  causes  of  hypertrophic  osteoarthrop- 
athy must  be  granted,  namely,  a  toxemia,  bacterial  or  otherwise,  and  stasis 
in  the  peripheral  circulation.  Either  may  induce  the  characteristic  changes, 
the  former  most  commonly,  or  both  may  act  together. 

The  condition  is  observed  most  frequently  in  early  adult  and  middle  life. 
From  the  study  of  all  reported  cases  Landis^^  found  the  ratio  of  males  to 
females  to  be  8:i.  There  were  but  three  negroes  among  117  cases  collected 
by  Emerson^. 

Morbid  Anatomy  of  Hypertrophic  Osteoarthropathy 

The  numerous  X-ray  studies  of  this  condition  in  recent  years  together 
with  a  considerable  number  of  post-mortem  examinations  have  given  us  a 
very  precise  conception  of  the  essential  features  of  the  pathology.  The 
pathological  picture  is  an  extremely  irregular  one  varying  somewhat  with 
the  nature  of  the  primary  disease  and  especially  with  the  degree  to  which 
the  bones  and  joints  are  affected. 

End  Phalanges. — It  is  usually  stated  that  the  typical  bulbous  enlarge- 


MORBID  ANATOMY  437 

ment  of  the  terminal  phalanges  of  the  fingers  and  toes  is  entirely  due  to 
changes  in  the  soft  parts.  This  is  undoubtedly  true  of  the  majority  of  the 
cases  of  club  fingers  without  changes  in  the  long  bones  although  a  small 
percentage  with  the  X-rays  show  an  unmistakable  alteration  in  the  first  row 
of  phalanges.  It  must  always  be  borne  in  mind  that  the  ungual  phalanges 
in  healthy  individuals  present  rather  extreme  variations  in  size  and  shape. 
Among  thirty-nine  cases  of  apparently  simple  clubbing  of  the  fingers 
studied  by  me,  the  X-rays  revealed  a  definite  proliferation  of  the  distal 
phalanges  in  five.  Three  occurred  with  chronic  pulmonary  tuberculosis, 
one  with  cardiac  disease  and  one  with  cardiac  disease  and  pulmonary 
tuberculosis.  Teleky^,  von  Bamberger^,  Kriiger^^,  Gouldesbrough^^,  Landis^^ 
and  Reynaud  and  Audibert^^  describe  similar  changes  as  rarely  occurring  in 
club  fingers.  In  the  more  advanced  cases  with  changes  in  the  long  bones 
this  hypertrophy  in  the  terminal  bones  of  the  fingers  is  much  more  common 
and  marked. 

The  alterations  in  the  end  phalanges  are  in  the  nature  of  an  irregular 
mossy  proliferation  confined  chiefly  to  the  distal  half  giving  to  the  bone 
a  "burr-like"  appearance.  Rarely  very  long,  spur-like  projections  are  observed. 

The  changes  in  the  soft  parts  are  much  more  striking.  The  nails  are 
greatly  thickened,  ridged  longitudinally  and  curved  in  both  directions 
sometimes  to  such  a  degree  as  to  offer  a  very  close  resemblance  to  a  parrot's 
beak.  The  nail  bed  is  full,  rounded,  smooth  and  injected.  A  uniform  thick- 
ening of  the  soft  tissues  gives  to  the  part  a  bulbous  appearance  like  the  end  of 
a  drum-stick,  hence  the  name  so  commonly  applied  of  "drum-stick  fingers." 
Actual  edema  probably  does  not  occur,  the  enlargement  being  due  to  various 
factors  including  proliferation  of  connective  and  fat  tissue  and  an  injection 
of  the  capillaries  about  the  nail  bed.  A  slight  amount  of  cellular  infiltration 
has  also  been  described.    The  finger  ends  are  usually  deeply  cyanosed. 

In  some  of  the  cases  of  advanced  hypertrophic  osteoarthropathy  the 
whole  hand  is  enlarged  in  addition  to  the  clubbing,  the  fingers  throughout 
their  length  being  increased  in  size  thus  giving  the  same  appearance  as  in 
gigantism. 

Changes  in  the  Long  Bones. — It  has  been  frequently  stated  that  the 
process  in  the  long  bones  does  not  begin  for  several  years  after  the  onset  of 
the  primary  disease.  This  observation  is  doubtless  correct  so  far  as  the 
advanced  stage  of  the  disease  is  concerned  but  it  seems  probable  that 
systematic  X-ray  examinations  of  the  bones  of  the  forearms  and  lower  legs 
in  cases  of  clubbed  fingers  would  establish  the  fact  that  changes  in  these 
parts  begin  much  earlier.  Among  thirty-nine  cases  of  club  fingers  studied  by 
me,  in  twelve  the  X-rays  showed  characteristic  subperiosteal  bony  prolifera- 
tion of  the  same  type  and  distribution  as  described  in  osteoarthropathy. 
In  a  series  of  thirty-two  patients  with  advanced  pulmonary  tuberculosis  and 


438  SECONDARY  OSTEOARTHROPATHY 

clubbing  of  the  fingers  KesseP^  found  exactly  the  same  changes  in  the  long 
bones  in  ten.  These  undoubtedly  represent  the  early  stage  of  the  typical 
changes  seen  in  the  well  developed  cases  of  Marie's  disease.  Von  Bamberger 
mentions  one  case  in  which  enlargement  of  the  lower  portion  of  the  tibiae 
with  pain  de\^loped  within  two  months  from  the  onset  of  the  primary'  dis- 
ease. I  have  recently  seen  a  man  of  thirty-five  who  had  had  pneumonia  nine 
months  previously,  followed  by  an  empyema  which  had  not  been  treated. 
Unusually  well  marked  clubbing  of  the  fingers  was  present  but  no  evidence 
of  changes  in  the  long  bones.  X-ray  examination  showed  a  thin  subperiosteal 
layer  of  new  bone  in  the  tibiae,  fibulae,  ulnae,  radii  and  nearly  all  of  the 
carpal  and  tarsal  bones. 

The  skeletal  changes  in  every  instance  probably  begin  in  the  distal  third 
of  the  diaphysis  of  the  ulna  and  tibia  but  with  the  advance  of  the  process 
nearly  the  entire  osseous  system  may  become  involved.  Numerous  X-ray 
studies  of  recent  years  have  revealed  a  degree  of  general  involvement  not 
previously  recognized.  Not  only  are  all  the  long  bones  and  those  of  the 
hands  and  feet  generally  affected  but  also  many  of  the  flat  bones  as  well  and 
even  the  vertebrae.  Changes  in  the  inferior  maxillarv'  bone  and  of  the  skull 
have  been  recorded.  A  moderate  degree  of  prognathism  is  described  in  one 
case. 

The  typical  process  in  the  bones  (Figs.  5  and  6)  consists  primarily  in  a 
slowly  progressive  ossifying  periostitis  beginning  in  the  distal  end  of  the  di- 
aphysis and  later  involving  the  entire  shaft.  There  is  constantly  a  thickening 
of  the  periosteum  which  is  deeply  injected.  The  layer  of  new  bone  is  very^ 
irregular  in  outline  and  appears  as  avery  distinct  sheath  enveloping  the  origi- 
nal shaft.  At  first  very  thin  and  poor  in  lime  salts  at  a  later  stage  of  the  dis- 
ease it  becomesvery  denseand  closely  united  with  thecortical  layer  of  the  old 
bone.  As  a  result  of  this  proliferation  the  bone  is  increased  in  size  in  rare  in- 
stances to  double  its  normal  diameter.  Thayer^^  found  an  increase  in  the 
length  of  the  affected  bones.  As  the  disease  progresses,  there  develops  hand  in 
hand  with  theossifyingperiostitisararefyingosteitis  of  the  old  shaft  w^hich  has 
been  observed  to  proceed  to  such  an  extent  as  to  entirely  destroy  the  normal 
structure  and  appearance.  This  was  the  condition  found  in  Case  i  of  my 
series  and  the  picture  in  the  X-ray  (Fig.  6)  except  for  the  absence  of  bowing 
was  quite  similar  to  that  seen  in  osteitis  deformans.  At  this  stage  the  mar- 
row space  is  often  entirely  obliterated.  Suppuration  never  occurs.  Cysts 
are  rarely  seen.  Osteophytes  near  the  costal  cartilages  are  not  uncommon. 
Beyond  the  early  stages  the  epiphyses  are  involved  along  with  the 
diaphyses  but  the  newly  formed  bone  is  of  much  more  irregular  type  and  less 
dense  than  the  old  bone.  Its  appearance  js  that  of  a  very  thick,  uneven, 
moss-like,  exuberant,  new  growth  which  stops  sharply  at  the  cartilage  edge. 
Alterations  in  the  soft  tissues  about  the  diseased  bone  are  marked  and 


Fig.  5. — Secondary  hypertrophic  osteoarthropathy. 
Male,  age  32.  X-ray  of  forearm  showing  characteristic 
irregular  subperiosteal  layer  of  new  bone  and  especially 
the  irregular  and  abundant  proliferation  of  new  bone 
about  the  epiphyses.    Original  shalt  unchanged. 


A.    Facing  438 


SYMPTOMS  439 

quite  unique.  The  swelling  is  of  such  a  high  grade  as  to  give  to  the  forearms 
and  legs  a  clumsy,  cylindrical  appearance.  This  results  largely  from 
hyperplasia  of  the  connective  tissue  but  edema  is  also  a  factor.  Muscular 
atrophy  of  a  high  grade  may  be  present  especially  in  the  hands. 

Joints.— The  involvement  of  the  joints  in  osteoarthropathy  is  more 
constant  than  usually  recognized,  perhaps  due  to  the  fact  that  it  is  a  rela- 
tively late  development.  In  some  instances  the  symptoms  in  the  articula- 
tions are  more  prominent  than  those  referable  to  the  long  bones  and  appear 
earlier  as  was  true  in  Case  i  of  my  series.  There  is  much  difference  of 
opinion,  especially  among  early  writers  on  this  point,  many  asserting  that  no 
change  takes  place  except  in  the  periarticular  tissues.  Recent  authors 
nearly  all  agree  that  at  least  in  all  well  developed  cases  the  joints  themselves 
participate  to  a  considerable  extent  in  the  morbid  process.  The  joints  most 
often  involved  are  those  adjacent  to  the  affected  bones,  i.e.,  the  wrists,  knees, 
ankles,  elbows  and  small  joints  of  the  hands  and  feet.  The  articulations  are 
enlarged  to  a  varying  degree  principally  as  a  result  of  the  swelling  of  the 
periarticular  tissues  and  the  presence  of  fluid  in  the  capsule.  The  effusion  is 
characteristically  intermittent  and  often  considerable  in  amount.  There  is, 
as  a  rule,  no  local  redness,  heat  or  acute  tenderness.  The  process  is  in  the 
nature  of  a  low  grade  synovitis  with  thickening  of  the  capsules  and  a  varying 
degree  of  erosion  of  the  cartilage.  In  a  few  cases  the  articular  ends  of  the 
bones  have  been  found  completely  denuded  of  cartilage,  though  as  a  rule  the 
cartilage  is  but  little  changed.  Ankylosis  may  occur  rarely  as  a  result  of  the 
bone  proliferation  in  the  neighborhood  of  the  articulation. 

Therese  (quoted  by  Thompson^^)  studied  the  chemistry  of  the  new  bone 
and  found  an  increase  in  magnesium  phosphate  at  the  expense  of  the  cal- 
cium salts  as  well  as  some  increase  in  the  organic  matter. 

Actual  absorption  of  the  new  bone  has  not  been  observed  to  accompany 
the  relief  of  symptoms  and  disappearance  of  swelling  in  the  soft  parts 
following  improvement  in  the  primary  disease.  Thompson^^  states  that  such 
a  process  does  not  occur.  I  have  in  two  cases  observed  a  very  considerable 
absorption  of  the  new  bone  as  demonstrated  by  means  of  X-rays  covering  a 
period  of  several  years.       The  endocrine  glands  are  normal. 


Symptoms  of  Hypertrophic  Osteoarthropathy 

Three  clinical  types  of  secondary  hypertrophic  osteoarthropathy  are 
usually  described,  following  Sternberg's  classification:  (i)  clubbing  of  the 
fingers  and  toes  without  changes  in  the  long  bones.  Subjective  signs  and 
symptoms  are  usually  wanting.  The  condition  may  be  secondary  to  any  of 
the  diseases  discussed  under  etiology;  (2)  von  Bamberger's  type  of  "a  higher 


440  SECONDARY  OSTEOARTHROPATHY 

grade,  namely,  a  combination  of  clubbing  with  painful  thickening  of  the 
long  bones  especially  of  the  forearms  and  lower  legs."  This  type  is  secon- 
dary to  the  same  diseases  as  is  type  i ;  (3)  Marie's  type  ("osteoarthropathie 
hypertrophiante")  or  a  stage  of  the  disease  where  the  condition  is  no  longer 
a  mere  incident  in  the  course  of  the  primary  disease  but  by  reason  of  the 
conspicuous  general  deformities  and  severe  symptoms  itself  comes  to  the 
foreground.  In  this  group  according  to  Sternberg^^  the  primary  disease  is 
often  not  prominent  and  may  even  be  undetermined. 

These  groups  in  the  light  of  our  present  knowledge  are  clearly  but 
different  stages  in  the  development  of  the  disease.  In  several  cases  which 
were  under  observation  for  some  years  I  have  watched  the  advance  from  one 
to  another  grade  and  any  attempt  at  definite  grouping  of  cases,  as  suggested 
by  Sternberg^^,  except  for  purposes  of  description  seems  to  me  unnecessary 
and  confusing. 

The  changes  in  the  ungual  phalanges  vary  from  the  beginning  thickening 
in  thesoft  parts,  occurringwithout  involvement  of  the  long  bones,  to  the  most 
extreme  type  of  clubbing  accompanying  advanced  stages  of  the  disease. 
When  the  disease  is  well  established  the  alterations  in  the  finger  ends  are  very 
striking  though  by  reason  of  the  absence  of  any  subjective  symptoms  the 
patient  is  usually  entirely  unconscious  of  their  presence.  The  onset  of  these 
changes  is  insidious.  As  a  rule  slowly  progressive  they  may  in  rare  instances, 
as  with  a  closed  empyema,  develop  with  extraordinary  rapidity  and  well 
marked  clubbing  be  present  in  the  course  of  a  few  weeks. 

In  the  average  case  of  simple  clubbed  fingers  the  deformity  is  sharply 
confined  to  the  distal  phalanx  and  is  almost  strictly  symmetrical,  the  two 
hands  showing  equal  involvement.  The  thumbs  and  forefingers  are  com- 
monly the  first  to  be  attacked  and  hence  when  the  condition  has  reached  a 
marked  stage  these  are  apt  to  present  a  considerably  greater  degree  of 
deformity.  Changes  in  the  toes  accompany  those  in  the  fingers  but  some- 
times not  until  the  latter  are  fairly  well  marked  and  then  the  great  toe  is 
always  disproportionately  involved.  The  enlargement  affects  both  diam- 
eters of  the  finger  tip  giving  it  a  globular  or  bulbous  appearance.  Occa- 
sionally the  increase  in  size  is  enormous,  Marie  recording  one  case  which 
measured  10  cm.  in  circumference.  The  skin  may  be  more  or  less  thickened 
but  is  otherwise  unchanged.  More  striking  are  the  alterations  in  the  nail. 
It  is  curved  both  transversely  and  longitudinally,  thickened,  and  frequently 
shows  rather  marked  irregularities  and  prominent  grooves  running  length- 
wise of  the  nail.  Not  infrequently  the  free  end  of  the  nail  is  sharply  hooked 
over  the  finger  end  in  form  resembling  a  parrot's  beak.  Other  nutritional 
disturbances,  as  indicated  by  increased  brittleness,  are  also  met  with.  In 
well  developed  cases  the  greatest  prominence  of  the  nail  is  at  about  its 
central  portion.    Varying  degrees  of  cyanosis  of  the  nail  are  the  rule.    The 


SYMPTOMS  441 

affected  nails  are  said  to  grow  more  rapidly  than  normal.  The  nail  bed  is 
raised,  abnormally  smooth  and  deeply  injected.  Pressure  over  the  root  of 
the  nail  gives  a  sensation  of  fluctuation  as  though  the  root  were  resting  on  a 
fluid  cushion.  At  this  stage  muscular  atrophy  in  the  fingers  often  accentu- 
ates the  clubbing. 

With  the  approach  of  a  later  stage  of  the  disease  and  accompanying  the 
process  in  the  long  bones  the  whole  hand  becomes  altered.  It  appears 
gigantic,  crude  and  "paw-like."  The  fingers  look  pufTy  and  are  sometimes 
moderately  spindle  shaped.  They  seem  stiff,  are  handled  clumsily,  muscular 
power  is  greatly  diminished  and  the  hand  cannot  be  closed  completely.  The 
general  appearances  in  the  hands  suggest  the  presence  of  arthritis  in  the 
joints  of  the  fingers  and  metacarpophalangeal  joints,  but  aside  from  a 
moderate  thickening  of  the  periarticular  tissues  and  slight  stiffness  or  very 
moderate  dull  pain  there  is  no  real  evidence  of  an  actual  arthritis.  Quite 
analogous  changes  occur  in  the  feet  but  are  less  evident  in  the  toes  than  in 
the  tarsus  and  ankle.  Von  Bamberger  has  aptly  suggested  the  term  "ele- 
phant foot"  for  the  most  extreme  type  of  deformity  in  the  foot.  The 
hands  and  feet  are  moist  from  excessive  sweating. 

When  the  long  bones  are  involved  the  clinical  picture  becomes  a  more 
complicated  one  and  the  symptoms  are  no  longer  solely  objective.  Pain  is 
the  most  prominent  and  constant  symptom  and  generally  develops  with  the 
appearance  of  swelling  in  the  legs  and  forearms  to  which  region  it  is  almost 
invariably  confined.  It  is  variously  described  by  the  sufferers  as  a  mere 
discomfort,  a  burning  or  prickly  sensation,  or,  more  commonly,  as  a  deep, 
dull  ache  in  the  bones  which  for  a  considerable  time,  at  least,  increases  in 
severity  as  the  disease  advances.  In  some  of  the  cases  of  long  standing  the 
pain  may  disappear  entirely.  It  is  apt  to  be  intermittent  occurring  for  short 
intervals  or  only  at  night  or  in  the  legs  after  long  standing.  More  rarely  the 
pain  is  constant  and  agonizing  as  indicated  by  a  few  reported  cases.  I  have 
only  once  met  such  an  extreme  case  and  then  the  pain  and  tenderness  were  of 
the  exquisite  type  so  common  to  rheumatic  fever.  Cold  accentuates  and 
warmth  relieves  the  pain.  The  patient  usually  finds  that  the  pain  in  the 
arms  and  legs  as  well  as  the  swelling  is  worse  during  the  periods  when  the 
primary  disease  is  most  active,  as  in  the  case  of  bronchiectasis  or  lung  abscess, 
when  the  sputum  is  most  abundant  and  purulent.  In  other  words,  the 
symptoms  of  the  secondary  disease  quite  definitely  run  a  course  parallel  to 
that  of  the  underlying  disease.  Sensitiveness  over  the  enlarged  bones  always 
accompanies  the  pain. 

The  evidence  of  bone  involvement  begins  in  the  distal  third  of  the 
forearms  and  lower  legs  and  it  is  in  these  regions  that  the  process  reaches  its 
most  extreme  degree.  When  fully  established  the  whole  forearm  and  lower 
leg  are  cylindrically  enlarged  and  of  about  the  same  diameter  throughout 


442 


SECONDARY  OSTEOARTHROPATHY 


Fig.  7).  A  moderate  degree  of  edema  may  be  present  and  in  the  most  acute 
cases  some  local  increase  in  temperature  is  associated  with  the  pain  and  ten- 
derness. In  its  extreme  development, 
that  is,  when  the  osseous  system  is  gen- 
erally affected,  the  disease  presents  a 
very  unusual  picture.  General  and  ex- 
treme emaciation  is  present,  likewise  a 
considerable  degree  of  anemia.  The  pa- 
tient is  weak,  holds  himself  stiffly  and 
moves  about  clumsily  as  a  result  of 
stiffness  in  the  spine  and  joints. 
Kyphosis  of  varying  degrees  may  exist. 

A  more  or  less  general  involvement 
of  the  joints,  similar  to  arthritis  in 
the  hands,  accompanies  the  late  stages 
of  the  disease.  Those  joints  adjacent 
to  the  most  marked  osseous  changes 
are  the  ones  showing  the  most  signs, 
i.e.,  the  wrists  and  ankles.  The  prin- 
cipal and  the  first  complaint  may  be 
of  pain  and  stifTness  in  the  articula- 
tions, usually  the  wrists  and  ankles. 
Actual  inflammation  of  the  joints  is 
seen  in  exceptional  cases.  The  acute 
symptoms  in  the  joints  are  invariably 
associated  with  an  elevation  of  tem- 
perature which  subsides  coincidently 
with  the  disappearance  of  the  symp- 
toms. Thompson^''  observed  enlarge- 
ment of  the  glands  in  the  axilla  and 
groin  associated  with  the  acute  stage 
of  the  process  in  the  wrist  and  joints 
of  the  lower  extremity.  He  regards 
the  process  in  the  joints  in  all  cases  as 
unquestionably  inflammatory  in  type. 
Subluxation  or  other  forms  of  disloca- 
tion are  unknown,  although  a  slight 
degree  of  hyperextension  is  mentioned. 
There  is  no  grating  in  the  affected  joints. 

Mention  has  been  made  of  the  parallelism  between  the  symptoms  of  the 
osteoarthropathy  and  the  course  of  the  primary  disease.  Two  cases  under 
my  observation  have  had  acute  exacerbations  of  a  very  noteworthy  type 


F'iG.  7. — Secondary  hypertrophic 
osteoarthropathy.  Male,  age  30.  Ob- 
serve the  clubbing  of  the  fingers  and 
toes  and  the  marked  cylindrical  en- 
largement of  the  lower  legs  and  fore- 
arms. 


DIAGNOSIS  443 

which  did  not  seem  dependent  on  an  exacerbation  in  the  primary  condition. 
There  was  a  sudden  onset  of  intense  pain  with  the  development  of  swelHng 
and  very  acute  sensitiveness  over  the  bones,  high  fever  and  great  prostration. 
This  acute  stage  lasted  for  two  or  three  weeks,  the  symptoms  then  gradually 
subsiding.  These  acute  attacks  bear  a  striking  resemblance  to  the  course  of 
rheumatic  fever. 

Painful  swelling  of  the  breast  similar  to  that  seen  in  males  at  the  time  of 
puberty  has  been  noted  by  von  Bamberger^.  Brooks^^  cites  several  cases  with 
bulbous  enlargement  of  the  nose  and  thickening  of  the  malar  region.  Kes- 
seP^  also  observed  these  in  six  of  his  ten  cases.  Skin  lesions  in  my  experience 
are  rare  but  Alexander^  mentions  ichthyosis,  eczema,  erythema,  pigmenta- 
tion and  rapid  growth  of  hair  on  the  affected  parts  as  occasionally  occurring. 
Organic  disturbances  except  as  associated  with  the  primary  disease  are 
unknown.  There  is  no  reaction  of  degeneration  in  the  muscles,  no  change  in 
the  reflexes  and  no  sensory  disturbances. 

The  course  of  the  disease  is,  like  its  clinical  types,  extremely  varied  and 
probably  depends  entirely  on  the  course  of  the  primary  disease.  All  symp- 
toms and  signs  may  disappear  if  the  lesions  in  the  lungs  or  elsewhere  pro- 
ducing them  are  cured.  Rarely  the  disease  follows  a  chronic  progressive 
course  without  discoverable  activity  in  the  antecedent  disease.  At  times 
after  a  period  of  activity  of  many  months  or  a  few  years  it  subsides  into  a 
quiescent  state.  Ordinarily  the  course  throughout  is  with  periods  of 
alternating  activity  and  inactivity.  The  duration  is  often  many  years  since 
the  disease  being  a  secondary  condition  has  no  direct  influence  on  the  general 
health. 

Diagnosis  of  Hypertrophic  Osteoarthropathy 

Diagnosis  presents  no  difficulties  since  the  well  marked  lesions  of  osteo- 
arthropathy can  hardly  be  confused  with  any  other  disease.  But  few 
diseases  present  objective  signswhich  are  so  absolutely  unique  and  character- 
istic. Clubbing  of  the  fingers  should  always  lead  to  an  examination  of  the 
bones  of  the  hands  and  feet  as  well  as  those  of  the  forearms  and  legs.  It  is 
only  by  this  means  that  it  is  possible  to  detect  the  early  stages  of  the  perios- 
teal proliferation  so  characteristic  of  the  aisease.  The  fairly  regular  sheath 
of  new  bone  is  met  with  in  no  other  condition.  The  combination  of  the 
clubbed  fingers  and  painful  thickening  of  the  long  bones-showing  the  peculiar 
subperiosteal  layer  of  bone  in  the  X-rays  and,  occurring  with  some  diseases 
of  the  lungs  and  rarely  with  other  conditions,  is  pathognomonic  of  the 
disease. 

The  resemblance  of  this  condition  to  acromegaly  is  only  a  superficial  one. 
Acromegaly  is  a  primary  disease.     The  peculiar  changes  in  the  face  are 


444 


SECONDARY  OSTEOARTHROPATHY 


wanting  in  osteoarthropathy.  The  hands  may  be  enlarged  and  clumsy  in 
osteoarthropathy  but  do  not  simulate  the  appearances  seen  in  acromegaly. 
Symptoms  referable  to  the  central  nervous  system  are  never  present  in 
osteoarthropathy.  Clubbing  is  unknown  in  the  latter  and  the  nails  are 
small.  The  alterations  in  the  long  bones  as  seen  in  the  X-rays  are  seldom 
pronounced  and  consist  merely  in  an  irregularity  of  outline  especially  in  the 
epiphysis  and  an  accentuation  of  the  prominences  marking  the  muscle  and 
tendon  attachments. 

In  occasional  cases  where  the  joint  symptoms  are  most  pronounced  the 
osteoarthropathy  may  be  mistaken  for  chronic  arthritis.  The  joints, 
however,  very  seldom  show  any  outspoken  evidences  of  inflammation  and  the 
deformities  so  common  to  chronic  arthritis  are  lacking.  Clubbing  of  the 
fingers  and  thickening  of  the  long  bones  are  never  seen  in  arthritis. 

Heberden's  nodes  likewise  should  never  be  confused  with  osteo- 
arthropathy. In  this  condition  clubbing  is  wanting  and  the  enlargement  is 
not  in  the  distal  portion  of  the  end  phalanx  but  about  the  joint  which  is  de- 
formed. These  nodes  are  due  to  an  osteoarthritis  of  the  joint  with  hyper- 
trophy of  the  bone  which  takes  the  form  of  osteophytic  outgrowths  on  the 
dorsal  surface  at  the  edge  of  the  joint  cartilage.  The  process  is  observed 
only  in  old  people  and  is  a  primary  affection. 


Treatment 

No  form  of  therapy  has  any  direct  effect  on  the  condition  itself,  though, 
as  mentioned  above,  relief  of  the  underlying  disease  often  leads  to  prompt 
improvement  in  the  bones  and  finger  ends.  For  the  pain  hyperemia  treat- 
ment by  means  of  the  application  of  heat  in  some  form  or  counterirritation 
is  indicated.  Analgesics  may  even  be  indicated  in  the  rare  cases  with  pain  of 
an  intense  type.  The  general  treatment  is  the  same  as  that  for  any  chronic 
debilitating  disease. 


Part  III 
OSTITIS  FIBROSA  CYSTICA 

Introduction 

Definition. — A  rare  chronic  degenerative  disease  of  the  bones  beginning 
in  late  childhood  and  characterized  by  extreme  metaplasia  of  osseous  into 
fibrous  tissue  with  the  formation  of  benign  giant-celled  tumors  and  cysts 
leading  to  marked  deformities  and  fractures. 

Synonyms. — Allgemeine  Hyperostose  des  Skelettes  mit  Cystenbildung 
(Virchow) ;  Osteomalacia  mit  Cystenbildung  (Hirschberg) ;  tumorbildende 
Ostitis  deformans  (Sternberg) ;  Ostitis  fibrosa  osteoplastica  (von  Reckling- 
hausen) ;  Ostitis  fibroplastica  (Franke) ;  Osteodystrophia  juvenilis  cystica 
(von  Mikulicz);  Chronic  osteomyelitis  fibrosa  cystica  (Bloodgood) ;  von 
Recklinghausen's  disease. 

This  disease  is  one  of  the  last  to  be  separated  from  the  miscellaneous 
and  confused  group  of  bone  conditions.  Credit  for  its  recognition  is  due 
to  Hirschberg^^  who,  in  1889,  published  under  the  title  "Zur  Kentniss  der 
Osteomalacic  und  Ostitis  Molacissans"  a  very  exact  description  of  the 
pathology  of  specimens  at  the  City  Hospital  in  Dresden  previously  con- 
sidered as  multiple  cystic  sarcoma.  He  mentions  as  cardinal  features  the 
long  course,  weakness  of  bones,  multiple  fractures  and  cyst  formation.  As 
to  the  nature  of  the  process  he  concludes  that  it  should  be  regarded  as  a  late 
stage  of  "osteomalacia  with  cyst  formation,  multiple  fractures  and  secondary 
development  of  sarcoma." 

Von  Recklinghausen^^,  however,  in  1891,  first  definitely  separated  ostitis 
fibrosa  from  other  bone  diseases  with  degeneration  and  weakness  of  osseous 
tissue.  Since  then  the  disease  has  been  studied  by  many  investigators  and 
a  relatively  larger  number  of  cases  have  been  described.  Bloodgood^,  in 
1 910,  collected  sixty-nine  typical  cases. 


Clinical  Types  of  Ostitis  Fibrosa  Cystica 

Two  distinct  clinical  types  are  recognized,  the  localized  form  in  which 
the  fibrosis  and  cyst  formation  are  confined  to  a  single  bone  and  the  rarer 
general  form  in  which  multiple  bones  are  involved  (Fig.  8).  RingeP'^  states 
that  there  are  only  thirty  cases  of  this  latter  type  in  the  literature. 

The  bone  cysts  which  are  constantly  found  in  ostitis  fibrosa  also  develop 
secondary  to  many  other  primary  pathological  conditions.    Silver^^  groups 

445 


446 


OSTITIS  FIBROSA  CYSTICA 


them  as  follows:  (i)  those  from  softening  in  malignant  tumors;  (2)  those 
due  to  bacterial  infections  (bone  abscess) ;  (3)  those  due  to  parasites  (cysti- 
cercus,  echinococcus) ;  (4)  those  with  rare  bone  diseases  (arthritis  deformans, 
senile  osteoporosis,  osteomalacia) ;  (5)  those  as  minor  symptoms  of  osteitis 
deformans,  or  general  symptoms 
of  ostitis  fibrosa;  (6)  those  with 
callus;  (7)  those  in  Barlow's 
disease. 

Etiology 

The  cause  of  the  disease  is 
still  undetermined.  Although 
benign  cysts  are  common  in  the 
early  years  of  life  true  ostitis 
fibrosa  rarely  develops  before  ten 
or  after  twenty.  Von  Mikulicz^", 
Konig^^  and  Bloodgood-  empha- 
size especially  the  fact  that  the 
vast  majority  of  cases  occur  be- 
fore the  twentieth  year,  i.e.,  dur- 
ing the  time  of  life  when  bone 
growth  is  active.  The  last  men- 
tioned author  found  but  five 
cases  among  the  sixty-nine  col- 
lected who  were  over  twenty  at 
the  time  of  onset.  Frangenheim^, 
however,  calls  attention  to  the 
fact  that  although  the  condition 
is  rarely  seen  until  after  the  tenth 
year  the  history  will  often  give 
evidence  that  the  process  existed 
much  earlier  but  was  unobserved. 
His  figures  of  published  cases  in- 
dicate that  fifty  to  sixty  per  cent, 
are  first  seen  during  the  second 
decade.  Clearly  the  disease  is  of 
slow  development  and  its  course 
in  the  average  case  covers  a 
period  of  years.    The  ratio  of  females  to  males  is  48:39  (Bloodgood). 

The  disease  has  been  explained  on  the  basis  of  various  etiologic  factors, 
heredity,    hereditary    syphilis,    toxic    conditions,     trauma,    perverted    in- 


FiG.   8. — Ostitis    fibrosa   cj'stica.     Skeleton 
of  woman  of  40.     (v.  Recklinghausen.) 


PATHOLOGY  447 

ternal  secretions,  inflammatory  nervous  diseases  and  rheumatism.  Rehn^^ 
holds  that  the  disease  results  from  bone  dystrophy,  i.e.,  an  overdevelop- 
ment of  a  physiological  process  as  in  callus,  rickets,  osteomalacia,  sarcoma 
and  senile  osteoporosis.  Our  present  knowledge  of  the  disease  will  not 
permit  any  definite  opinion  as  to  the  cause,  but  it  seems  most  reasonable  to 
regard  the  disease  as  such  a  dystrophy  of  growing  bones  in  which  a  chronic 
inflammation  plays  a  prominent  part  (von  Mikulicz^^-  21^  Tietza^'',  Blood- 
good^  Murphy2^).  As  a  result  of  a  careful  study  of  all  reported  cases 
Bloodgood  says,  "I  agree  with  all  the  more  recent  investigators  that  the 
disease  is  an  inflammatory  one." 

There  seems  to  be  abundant  evidence  that  trauma  and  probably  also  the 
resulting  hemorrhage  plays  some  and  perhaps  an  important  part  in  the 
formation  of  the  cysts  (von  Recklinghausen^^,  Franke^,  Monckeberg^^,  Blood- 
good^,  von  Mikulicz^i,  Hartmann").  Bolognesi^  conducted  a  long  series  of 
experiments  on  rabbits  in  an  attempt  to  produce  bone  cysts  by  various 
forms  of  trauma.  The  author  interprets  his  negative  results  as  a  refutation 
of  the  theories  of  a  traumatic  or  infectious  origin  of  cysts. 


Pathology 

The  main  features  of  the  pathological  changes  in  the  bones  are:  (i)  a 
general  and  diffuse  degeneration  and  absorption  of  the  old  bone;  (2)  a 
curious  growth  of  connective  tissue;  (3)  development  of  benign  spindle- 
celled  sarcomas;  (4)  formation  of  cysts;  and  (5)  occurrence  of  spontaneous 
fractures  (Hirschberg^^,  von  Recklinghausen^^,  Monckeberg^^,  Pfeiffer^^, 
Rehn26,  Gaugele^",  Tietza^°,  Fiijii^  Hartmann^^  Lissauer^*,  Brunn^ 
Matsouka^^,  Bolognesi^  Frangenheim'^,  Saurborn^^). 

The  bones  involved  in  the  localized  form  of  ostitis  fibrosa  are  the  long 
ones.  Most  commonly  the  humerus,  femur  and  tibia  are  the  seat  of  the 
lesions.  In  the  generalized  form  practically  the  entire  skeleton  may  parti- 
cipate. The  skull,  which  usually  escapes,  in  one  of  von  Recklinghausen's 
cases^  (Case  5)  showed  an  irregular  and  unsymmetrical  involvement.  In 
consequence  of  the  tumor  formation  and  fractures  the  individual  bones  in 
both  forms  are  greatly  altered  in  size  and  shape  (Figs.  9  and  10).  The  pro- 
cess is  confined  to  a  portion  of  the  bone  only,  usually  the  proximal  end. 
The  bowing  in  the  upper  and  lower  extremities  is  of  a  very  angular  and  ir- 
regular kind. 

The  very  complex,  interosseous  lesions  found  are  confusing,  and  the 
relationship  and  sequence  of  the  various  changes  are  not  fully  understood. 
The  earliest  process  is  probably  a  degeneration  of  bone  of  high  degree  due 
to  lacunar  absorption  beginning  in  the  metaphesis.    This  bone  destruction  is 


448  OSTITIS  FIBROSA  CYSTICA 

accompanied  by  an  irregular  new  formation  of  fibrous  tissue.  The  bone 
presents  a  most  unusual  picture.  On  section  it  shows  a  varied  mixture  of 
remains  of  old  bone,  widely  scattered  connective  tissue  islands,  small 
remains  of  cartilage,  deep  injection  of  the  tissue  or  even  hemorrhages  and, 
finally,  cysts.  The  marrow  shows  clearly  the  evidence  of  a  fibrous  meta- 
plasia of  all  grades.  In  appearance  it  may  even  suggest  fibroma.  In  general 
the  normal  compact  substance  of  the  diaphysis  is  replaced  by  a  fine  or 
coarse  connective  tissue  rich  in  fibroblasts.  The  epiphysis  is  much  less 
altered.  It  is  evident  from  the  character  of  the  bone  that  transudates  and 
hemorrhage  play  a  prominent  part.  The  periphery  of  the  bone  show^ 
equally  marked  degenerative  changes.  Instead  of  the  dense  compact  bone 
one  finds  an  extremely  irregular  structure  with  many  small  cavities,  scat- 
tered trabeculae,  Volkman's  perforating  canals,  Howship's  lacunae  and 
everA-^vhere  fibroosteoid  tissue.  In  places  the  cortex  is  only  the  thickness 
of  parchment. 

The  periosteum  does  not  appear  in  any  way  to  react  to  the  disease  until 
fracture  occurs  when  it  participates  in  the  healing  process  by  callus  forma- 
tion. As  a  whole  the  osseous  tissue  contains  less  lime  than  normal  and  in 
consequence  the  bone  can  be  readih'  bent  or  depressed.  A  "rubber^^  flexi- 
bility" has  been  described.  The  metaplasia  into  fibrous  tissue  is  often  so 
extreme  that  small  or  large  tumors  are  found.  Because  of  the  abundant 
giant  cells  present  in  these  tumors  they  are  called  "giant-celled  sarcomas." 
They  are,  however,  benign. 

The  cysts  (Fig.  lo)  are  usually  found  in  the  shaft  of  the  long  bones  near  the 
epiphyseal  end  though  very  rarely  in  the  skull  and  fiat  bones  also.  The  most 
characteristic  form  is  the  small,  smooth-walled,  rounded  type.  In  the  cysts 
of  long  standing  the  bony  wall  becomes  extremely  thin  or  if  peripherally 
placed  may  have  only  a  wall  of  periosteum.  There  is  no  true  epithelial 
lining  though  a  few  possess  an  indefinite  coxnering  of  connective  tissue  cells. 
A  few  instances  of  multiple  cysts  have  been  recorded.  The  contents  are 
whitish  to  a  deep  brown,  consisting  of  gelatinous,  cheesy  or  serous  material. 
Actual  hemorrhagic  fluid  is  never  found  (Bloodgood). 

The  origin  of  the  cysts  was  attributed  by  Vircho\\-^^  to  the  breaking 
down  of  remains  of  cartilage  either  new  formed  or  from  remnants  of  the 
epiphyseal  cartilage.  Von  Recklinghausen's  theory  that  the}-  arise  from 
degeneration  and  softening  of  the  fibrous  tumors  is  generally  accepted  (von 
Recklinghausen^',  Konig^^,  Heineke^-,  Monckeberg"--,  Lissauer^^,  Tietza^", 
Matsouka^^,  Bloodgood^,  Fiijii^).  Evidence  strongly  points  to  trauma  and 
hemorrhage  as  important  but  not  the  only  factors  in  causing  cysts  (Franke^ 
von  Mikulicz^"' 21^  Konjetzuy^S  Jenckel'^  Landon^^  Bolognesi^).  On  the 
basis  of  this  conception  Frangenheim  considers  the  cysts  as  the  last  stage  of 


Fig    q -Ostitis  fibrosa  cystica.     Male,  age  i8  years.  _  X-ray  of  left  femur  showing 
uniform  thickening,  bowing,  fractures  and  striking  alterations  in  bone  structure.     (Case 
of  Dr.  R.  W.  Lovett.) 
A,    Facing  448 


Fig.  I o.— Ostitis  fibrosa  cystica.  Female,  age  8  years.  X-ray  of  right  humerus 
showing  in  upper  half  enormous  thickening,  irregular  outline  and  general  thinning 
of  bone  with  multiple  cysts.     (Case  of  Dr.  A.  W.  George.) 


B.     Facing  448 


SYMPTOMS  AND  COURSE  449 

the  process  in  ostitis  fibrosa.      Von  Mikulicz-"  believes  that  the  develop- 
ment of  cysts  is  a  matter  of  years. 

Spontaneous  fractures  or  fractures  resulting  from  insignificant  trauma 
inevitably  occur  as  a  result  of  the  weakening  of  the  bone  (Fig.  9).  Blood- 
good^  found  only  a  single  case  of  ostitis  fibrosa  where  fracture  was  not  present. 
The  fracture  is  very  frequently  multiple.  A  rich  callus  formation  is  always 
to  be  expected  and  prompt  healing  results.  Von  Bergmann^  considers  that 
the  breaking  of  the  cyst  wall  with  fracture  acts  as  a  strong  stimulant  to 
the  growth  of  new  bone. 


Symptoms  and  Course 

In  common  with  many  other  bone  diseases  characteristic  symptoms  are 
not  prominent.  Symptoms  usually  appear  late  in  its  course  or  rarely  are 
wanting  throughout  and  are  in  general  those  common  to  intramedullary 
disease.  It  may  safely  be  assumed  that  the  bone  has  been  the  seat  of  disease 
for  at  least  several  months  if  not  years  prior  to  the  advent  of  symptoms. 

A  trifling  injury  may  produce  a  fracture  and  first  call  attention  to  the 
process  in  the  bone.  Von  Brunn^  finds  this  one  of  the  earliest  symptoms. 
Spontaneous  fracture  has  occurred  in  thirty-five  of  the  recorded  cases 
according  to  Silver^^  It  is  most  frequently  seen  when  the  humerus  or  femur 
is  the  seat  of  the  disease.  A  few  examples  of  incomplete  fracture  are  recorded. 

Pain  was  the  first  symptom  in  twenty-five  per  cent,  of  the  cases  collected 
by  Silver-^.  It  is  variously  described  as  "rheumatic,"  "dull,"  or  "aching,"  and 
less  often  as  mere  lameness  or  stiffness.  This  symptom  is  never  distressing. 
Rest  affords  relief.  Tenderness  may  be  present  over  the  cyst.  The  joints 
are  unaffected. 

As  the  disease  progresses  deformity  appears.  The  bone  is  swollen  in  the 
region  of  the  cyst  and  occasionally  reaches  enormous  size  (Figs.  9  and  10). 
Bowing  of  a  more  or  less  angular,  irregular  type  and  confined  to  a  fraction 
of  the  shaft  is  .often  observed.  Von  Brunn^  reports  in  a  girl  of  ten  an  extra- 
ordinary case  of  ostitis  fibrosa  of  both  femora  with  multiple  fractures  and 
resulting  coxa  vera  of  such  marked  degree  that  the  legs  were  crossed.  Short- 
ening may  result.  When  several  of  the  long  bones  are  involved  more  general 
deformity  develops  (Fig.  3).  With  marked  changes  in  the  bone  atrophy  of 
the  leg  or  arm  has  been  seen.  Bloodgood^  mentions  a  limp  as  one  of  the 
rare  symptoms.  A  moderate  degree  of  disability  may  result  from  the 
deformities. 

Metastases  from  the  tumors  have  never  occurred.  Complications  are  not 
described.  The  course  is  chronic  and  marked  by  the  occurrence  of  one  or 
Vol.  IV  29 


450  OSTITIS  FIBROSA  CYSTICA 

more  fractures  with  increasing  deformity.     Bloodgood  gives  a  duration  of 
eighteen  months  to  eighteen  years. 

X-rays  are  of  the  first  importance  in  this  disease  as  a  differential  diag- 
nosis is  practically  impossible  without  them.  The  cyst  cavity  is  clearly 
shown  usually  as  a  single  smooth,  rounded,  transparent  area  which  cannot 
readily  be  confused  with  any  other  condition.  The  medullary  cavity  of  the 
bone  is  partially  or  completely  obliterated  and  the  shaft  shows  typical 
atrophy  with  scattered  coarse  trabeculae  running  longitudinally.  The  epi- 
physis except  in  the  most  advanced  cases  is  normal.  The  outline  of  the  bone 
is  regular  and  the  periosteum  continuous. 


Diagnosis 

Ostitis  fibrosa  may  easily  be  confused  with  osteomalacia,  osteitis  de- 
formans, tuberculosis,  syphilis,  bone  abscess  and  certain  types  of  new 
growths  of  bone,  particularly  the  osteosarcomas,  and  a  definite  diagnosis  in 
the  early  stages  is  sometimes  impossible.  The  following  characteristic 
features  of  the  disease  are  important  to  bear  in  mind  in  differentiating  the 
condition  from  the  above.  The  disease  almost  invariably  appears  between 
the  tenth  and  twentieth  year.  Symptoms  are  in  the  background.  A  history 
of  slight  trauma  with  resulting  fracture  is  usually  present.  The  angular, 
localized  deformity  of  the  bones  with  irregular  enlargement  usually  of  the 
proximal  one-third  and  the  absence  of  local  symptoms  of  inflammation  are 
seldom  seen  in  any  other  disease.  The  disease  affects  almost  exclusively  the 
femur,  humerus  and  tibia  and  even  in  the  generalized  form  these  are  the 
bones  showing  the  most  marked  and  characteristic  alterations  in  size  and 
shape.  Spontaneous  fractures  are  particularly  prominent.  A  long  course 
with  increasing  deformity  but  without  the  appearance  of  severe  symptoms 
is  the  rule.    The  radiographic  appearances  are  unique. 

Osteomalacia  occurs  almost  exclusively  in  females  and  seldom  until  after 
twenty.  Pain  and  tenderness  over  the  bones  are  more  prominent  symptoms. 
The  bones  most  constantly  affected  are  those  of  the  pelvis.  The  deformity 
is  more  general  and  extreme.  Disturbance  of  gait  and  finally  a  condition  of 
almost  complete  helplessness  develop.  Cysts  do  occur  but  with  less  con- 
stancy. The  histological  picture  in  the  two  diseases  is  in  most  features 
entirely  different.  Roentgenograms- show  quite  distinct  differences  in  the 
two  conditions. 

Osteitis  deformans  (see  Part  i  of  this  Chapter). 

Tuberculosis  of  the  bone  is  confined  to  the  epiphysis  and  the  local  signs 
are  usually  quite  different.  The  roentgenographic  examination  readily 
excludes  tuberculosis. 


TREATMENT  451 

Syphilis  localized  in  one  of  the  long  bones  may  strongly  suggest  ostitis 
fibrosa  but  the  clinical  picture,  the  X-ray  appearances  and  the  Wassermann 
test  should  serve  to  prevent  any  confusion  of  the  two  conditions. 

Bone  abscess,  as  in  the  case  of  other  inflammatory  bone  processes,  gives 
local  signs  of  secondary  reactions.  The  deformity  of  ostitis  fibrosa  is  never 
simulated  by  abscess.  The  X-rays  show  in  the  medulla  of  the  shaft  a 
central  area  of  softening  with  irregular  walls,  often  with  sequestrum  and 
marked  bone  proliferation,  especially  peripherally,  beneath  the  periosteum. 

Sarcoma  of  the  hone  is  the  variety  of  malignant  tumor  most  commonly 
confused  with  ostitis  fibrosa.  The  disease  nearly  always  remains  confined  to 
a  single  bone.  Both  the  local  and  general  reaction  is  more  severe.  In  the 
X-rays  the  process  is  more  irregular  and  does  not  show  the  characteristic 
appearances  seen  in  ostitis  fibrosa  and  described  above.  The  cortex  is 
broken  through  with  the  result  that  the  surface  is  roughened. 

Treatment 

Treatment  is  primarily  surgical  and  the  results  of  operative  intervention 
have  been,  generally  speaking,  good.  Fractures  should  be  treated  as  any 
other  fractures.  Repair  is  practically  always  prompt  and  complete.  Among 
the  methods  of  operative  treatment  advised  are  aspiration,  curettage, 
osteotomy  and  excision  in  the  case  of  the  small  bones.  The  operation  of 
choice  is  to  open  the  cyst  and  curette  out  the  diseased  bone.  Excision  is 
rarely  indicated. 

Immobilization  of  the  affected  part  is  occasionally  necessary.  Pro- 
phylaxis in  the  form  of  protection  to  the  region  involved  and  the  regulation 
of  the  activities  of  the  patient  to  the  end  that  dangers  of  fracture  from 
trauma  be  minimized  is  important.  General  hygienic-dietetic  measures 
should  not  be  neglected. 

Bookman^  quotes  a  case  showing  marked  calcium  retention  with  evi- 
dence of  general  improvement  following  the  administration  of  calcium 
lactate  and  suggests  that  the  value  of  calcium  therapy  should  be  tested. 


Part  IV 
OSTEOPSATHYROSIS  (OSTEOGENESIS  IMPERFECTA) 

Introduction 

Definition. — Osteopsathyrosis  is  a  rare  condition,  probably  congenital 
in  origin,  appearing  most  commonly  in  fetal  life,  somewhat  less  frequently 
in  infancy  and  very  rarely  in  childhood  and  adult  life.  The  disease  pri- 
marily affects  the  bony  tissues  and  is  characterized  pathologically  by  a 
deficient  and  abnormal  bone  development  and  clinically  by  multiple  spon- 
taneous fractures  of  the  bones  of  the  arms,  legs  and  ribs. 

Synonyms. — Osteopsathyrosis  idiopathica  (von  Lobstein,  1833);  osteo- 
genesis imperfecta  (Volrik,  1845);  fetal  rickets;  rachitis  annularis;  osteo- 
porosis foetalis  (Kundrat);  osteomalacia  congenita  (Jurgen,  Marchand); 
dysplasia  periostalis  foetalis  (Klebs) ;  fragilitas  ossium  (Klebs) ;  periostale 
dystrophia  (Porak  and  Durante);  periostale  dysplasie  (Durant);  perios- 
tale aplasia  (S.  Muller);  pseudochondritis  (Schildowsky) ;  myeloplastische 
Malazie  (von  Recklinghausen) ;  ostitis  parenchymatosa  chronica  (Schmidt) ; 
osteogenesis  imperfecta,  congenita  and  tarda  (Looser);  Lobstein's  disease. 

This  imposing  array  of  terms  gives  evidence  of  the  confusion  which 
,  has  existed  in  the  past  regarding  the  nature  of  this  disease  and  its  relation 
to  other  bone  affections  occurring  in  fetal  and  early  life.  In  the  earlier 
writings  many  cases  of  this  condition  were  undoubtedly  described  as  a 
congenital  form  of  osteomalacia,  or,  more  commonly,  as  fetal  rickets. 
All  modern  authors  are  agreed  that  osteopsathyrosis  is  in  no  way  even 
indirectly  related  to  either  rickets  or  osteomalacia. 

The  first  case  ot  osteopsathyrosis  was  published  by  Amand  in  1716 
as  "intrauterine  fractures  without  preceding  trauma"  (quoted  by  Gurlt). 
Von  Lobstein^'''  in  1833  gave  the  first  accurate  clinical  description  of  the 
cases  occurring  in  infants  and  children  with  general  fragility  of  the  bones. 
A  detailed  description  of  the  alterations  in  the  form  of  the  bones  as  well 
as  in  their  structure  is  given.  He  explains  the  pathogenesis  on  the  basis 
of  an  "inertia  of  function."  Von  Lobstein  was  also  the  first  to  recognize 
the  influence  of  heredity  in  this  condition.  On  the  basis  of  the  changes 
found  in  the  bones  this  author  gave  to  the  condition  the  name  "osteop- 
sathyrosis idiopathica"  meaning  an  idiopathic  fragility  of  the  bones. 
In  1845  Vrolik^^  suggested  the  name  osteogenesis  imperfecta  as  best  de- 
scribing the  pathological  conditions  found  and  it  is  under  this  designation 
that  many  of  the  cases  have  been  reported. 

The  most  exhaustive  discussion  of  the  subject  among  the  earlier  writers 

452 


INTRODUCTION  453 

is  found  in  Gurlt's  Handbuch^^,  published  in  1862,  The  author  gives  a 
careful  analysis  of  all  recorded  cases  and  makes  important  contributions 
to  the  nature  of  the  disease  and  its  relation  to  other  diseases  of  fetal  and 
early  life  affecting  the  bones.  From  the  cases  collected  he  assembles 
conclusive  evidence  of  the  hereditary  factors  in  etiology.  Since  1862  the 
disease  has  been  the  subject  of  many  careful  studies  and  numerous  note- 
worthy articles  have  appeared.  Griffith^^  in  1897  succeeded  in  collecting 
67  cases  from  the  literature  and  in  1914  Ostheimer^^  added  126  subsequently 
published,  making  a  total  of  193.  The  disease  is  much  more  rarely  seen, 
however,  than  this  relatively  large  number  of  cases  would  seem  to  indicate. 
Birnbaum*  among  45,000  births  in  the  Gottingen  Frauenklinik  found  but 
a  single  instance  of  osteopsathyrosis. 

Increased  fragility  of  the  bones  of  varying  but  usually  moderate  de- 
gree is  seen  in  symptomatic  or  secondary  form  with  a  considerable  variety 
of  diseases,  old  age  (senile  osteoporosis),  bone  diseases  (osteitis,  osteo- 
malacia, osteomyelitis,  rickets,  hereditary  syphilis,  tuberculosis,  malig- 
nant diseases,  echinococcus  and  other  cysts),  trophic  neurologic  diseases 
(locomotor  ataxia,  poliomyelitis,  syringomyelia),  mental  diseases,  scurvy 
and  phosphorus  poisoning.  Brittleness  when  it  occurs  with  any  of  the 
above  conditions  is  readily  explained  by  obvious  alterations  in  the  bone 
as  a  result  of  the  primary  diseases. 

Types   of  Diseases 

Three  types  of  the  disease  have  been  described:  (i)  the  fetal  form  (osteo- 
genesis imperfecta  or  fetal  osteopsathyrosis)  (Fig.  ii)  in  which  the  fractures 
are  chiefly  intrauterine,  the  child  often  being  premature  and  either  still- 
born or  not  long  surviving  after  birth;  (2)  the  infantile  form  (infantile 
or  idiopathic  osteopsathyrosis)  appearing  in  children  who  show  no  frac- 
tures until  a  year  or  two  after  birth ;  (3)  the  adult  form  (idiopathic  osteop- 
sathyrosis) met  with  as  an  idiopathic  fragility  of  the  bones  after  childhood 
(Fig.  12). 

Bamberg  and  Huldschlnsky^  found  the  ratio  of  the  number  of  the 
fetal  type  to  the  later  form  to  be  approximately  i  :3.  Looser^^  separates 
the  cases  into  two  general  groups,  namely,  osteogenesis  imperfecta  congenita 
and  tarda.  Any  such  division,  however,  is  of  value  only  for  purposes  of 
description  as  nearly  all  modern  writers  are  agreed  that  there  is  no  essen- 
tial difference  in  the  disease  as  seen  at  different  ages  (Schuchardt^S  Nathan^^, 
Ziegler^^,  Looser^^,  Frangenheim^,  Sumita^",  von  Bamberg  and  Huld- 
schinsky^,  Schwarz  and  Bass^^,  Kienbock^^,  MixselPS  Hess^^  and  others). 
Both  the  clinical  picture  and  the  pathological  anatomy  in  the  congenital 
and  later  forms  are  identical  except  for  such  slight  variations  as  can  be 


454 


OSTEOPSATHYROSIS 


explained  on  the  basis  of  the  difference  in  the  stage  of  development. 
Looser^^  and  Kienbock^^  especially  emphasize  the  fact  that  all  possible 
transitional  cases  between  the  two  have  been  observed.  Hess^*  suggests 
that  the  osteopsathyrosis  appearing  in  later  years  is  but  a  latent  form 
of  the  usual  congenital  type  as  in  the  case  of  hereditary  syphilis  where 


Fig. II 


Fig. 12 


Fig.  II. — Osteopsathyrosis  congenita.  Skeleton  of  seven  months  fetus.  Note  the 
innumerable  fractures.      (Warren  Museum, .Harvard  Medical  School.) 

Fig.  12. — Osteopsathyrosis.  Adult  form.  Skeleton  of  woman  of  2i.  Note  multiple 
fractures  and  resulting  deformities.    (Warren  Museum,  Harvard  Medical  School.) 


the  evidences  of  the  disease  develop  at  birth  or  only  after  a  longer  or 
shorter  latent  period.  Looser^^  believes  that  the  osteopsathyrosis  of  adults 
is  the  result  of  congenital  bone  changes. 


PATHOLOGY  455 


Etiology 

The  actual  cause  is  undetermined.  The  sexes  are  about  evenly  divided, 
the  males  according  to  Ostheimer^*  comprising  fifty-three  per  cent,  of 
the  reported  cases.  Heredity  seems  to  be  an  etiologic  factor  of  some 
importance.  Both  von  Lobstein^^  (1834)  and  Gurlt^^  (1862)  emphasized 
the  fact  that  in  this  form  of  bone  fragility  there  is  often  striking  evidence 
of  hereditary  influence.  Since  the  time  of  these  early  writers  much  evi- 
dence has  accumulated  to  prove  that  a  family  tendency  in  osteopsathyrosis 
plays  a  role  of  some  importance  although  it  in  no  way  actually  explains 
the  disease.  Griffith^^  found  that  eighteen  among  sixty-seven  collected 
cases  gave  a  history  strongly  suggesting  family  predisposition.  Trans- 
mission is  usually  through  the  male  side.  Gurlt  presents  evidence  that  the 
tendency  may  rarely  be  passed  on  to  the  male  members  through  unaf- 
fected females. 

No  constant  changes  in  the  central  nervous  system  or  endocrine  glands 
have  been  found  to  explain  the  changes  in  the  bones.  Syphilis  is  not  a 
factor.  Kienbock^^  expresses  the  opinion  that  in  the  idiopathic  form  of 
osteopsathyrosis  the  nature  of  the  changes  in  the  skeleton  suggests  that 
the  disease  is  not  a  primary  bone  affection  but  one  of  some  central  organ 
(osteotrophic  organ)  which  furnishes  some  substance  necessary  for  the 
normal  formation  and  nutrition  of  the  bones.  Biggs^  regards  the  disease 
as  probably  of  nervous  origin  and  therefore  to  be  considered  a  neuropathic 
affection.  The  opinion  of  Harbitz^^  that  the  disease  must  be  considered 
as  due  to  some  disturbance  of  nutrition  afifecting  the  entire  bone  system 
during  fetal  life  seems  the  most  reasonable  one. 


Pathology 

In  this  disease  the  pathology  is  essentially  concerned  with  the  skeleton 
which  to  a  varying  degree  is  affected  throughout  (Figs,  ii  and  12).  The 
bones  both  in  their  outward  form  and  abnormal  internal  structure  are  en- 
tirely unlike  those  of  any  of  the  other  so-called  bone  diseases.  Though 
presenting  a  great  variety  of  changes,  especially  at  different  ages,  a  fairly 
definite  and  characteristic  picture  may  be  described.  The  bones  showing 
the  most  marked  alterations  are  those  of  the  extremities  and  ribs. 

As  a  rule  the  bones  develop  normally  in  length  but  often  become 
shortened  in  consequence  of  bowing  and  fractures.  They  appear  thin  and 
delicate.  The  diaphysis  may  be  straight  and  cylindrical  or  flattened  and 
greatly  deformed.    Actual  bowing  independent  of  fractures  does  occasion- 


456  OSTEOPSATHYROSIS 

ally  occur  (Kienb5ck).  The  most  characteristic  outv\^ard  feature  of  the 
long  bones  is  the  angular  deformities.  The  diaphysis  is  soft  and  brittle 
but  almost  never  shows  any  increased  flexibility.  No  epiphyseal  enlarge- 
ment is  present. 

The  head  is  usually  described  as  of  normal  size  and  shape.  Frangen- 
heim^  speaks  of  a  very  rare  hydrocephalic  type.  The  cranium  (Fig.  ii) 
shows  a  more  or  less  complete  absence  of  calcification,  in  extreme  cases  ap- 
pearing only  as  a  membranous  sac  (calvaria  membranacea).  In  other  cases 
the  calvarium  is  made  up  of  a  "mosaic  of  tiny,  irregular  bone  islands."  On 
the  other  hand,  the  bones  of  the  face  and  skull  base  are  much  more  nearly 
normal.  A  small  and  relatively  long  thorax  is  common.  Calcification 
has  taken  place  but  the  ribs  are  delicate  and  flexible.  They  are  frequently 
the  seat  of  numerous  fractures.  Deformities  in  the  spine  are  rare  but 
kyphoscoliosis  has  been  described  by  Kienbock^^  and  Niklas^^  The  pelvis 
may,  to  some  extent,  take  the  form  so  typical  of  osteomalacia. 

"The  stability  of  the  skeleton  is  markedly  diminished  and  instead  of 
acting  as  a  framework  for  the  body,  it  is  the  most  delicate  and  fragile 
part"  (Nathan).  Fragility  is  common  to  all  the  bones  but  fractures  are 
almost  entirely  confined  to  the  long  bones  of  the  extremities  and  to  the 
ribs.  The  bones  present  an  absolutely  unique  outward  appearance.  They 
are  grossly  deformed  showing  sharp  angulations,  irregular  curves  and, 
most  striking  of  all,  numerous  annular  thickenings  due  to  callus  forma- 
tion following  fractures.  Hohlfeld^^  likens  the  long  bones  thus  changed 
to  a  bamboo  rod.  Kienbock^^  divides  the  so-called  fractures  into  fissures, 
infractions  and  true  fractures.  It  is  usually  stated  that  callus  formation 
is  prompt  and  healing  takes  place  in  many  cases  more  quickly  than  normal. 
The  periosteum  is  but  rarely  ruptured.  Kienbock,  however,  contends 
that  healing  is  characteristicalh-  slow  and  may  not  be  complete  even 
after  several  months.  He  also  states  that  instead  of  union  actual  re- 
sorption of  the  ends  of  the  fragment  often  takes  place.  Sometimes  in  the 
place  of  a  firm  callus  there  exists  an  encircling  band  of  decalcified  bone. 
Similar  and  even  more  extensive  changes  result  when  dislocation  of  the 
fragments  is  present.  The  callus  is  largely  of  periosteal  origin.  In  the 
late  stages  of  the  disease,  according  to  this  author,  the  periosteal  callus 
may  be  greatly  hypertrophied.  The  total  number  of  fractures  as  indicated 
by  the  number  of  calluses  present  is  extremely  variable  but  frequently 
thirty  or  more.     Mixsell-^  quotes  the"  case  of  Chaussier  with  113  fractures. 

The  microscopic  changes  in  the  bones  have  been  carefully  studied  by 
Stilling29,  Harbitzl^  MicheP",  Biggs^  Ziegler32,  Looser^^,  Lovett  and 
Nicholses,  Sumita^o,  Fuchs^o,  Frangenheim^,  Nicklas^^,  Kienbocki^,  MixselPi 
and  others.  On  section  the  bones  are  soft  and  porous  but  these  changes 
are  confined  to  the  shaft.     The  epiphysis  and  epiphyseal  cartilages  are 


SYMPTOMS  457 

normal  in  form  and  structure  until  in  the  later  stages  the  cartilage  may 
give  evidences  of  degenerative  changes.  Most  observers  have  found 
normal  enchondrial  bone  formation  but  sometimes  small  in  amount. 

The  cortex  is  commonly  thin  and  friable.  The  spongiosa  shows  very 
unusual  general  markings.  Here  and  there  are  seen  small  irregular  islands 
of  cartilage.  Entire  absence  of  trabeculae  is  often  noted  and  if  present 
they  are  small,  irregular  in  outline  and  imperfectly  laminated.  Osteo- 
blasts are  much  diminished  in  number  and  size  and  appear  to  deposit 
only  a  thin  layer  of  osteoid  tissues  which  is  incompletely  calcified  (Nathan). 
Some  authors  have  found  the  osteoclasts  greatly  increased.  The  peri- 
osteum is  thin  and  functionally  inactive.  Large  marrow  spaces  replace 
the  normal  Haversian  system  (Nichols).  Biggs^  has  pointed  out  the  im- 
portant fact  that  the  absorption  of  bony  tissue  is  not  replaced  by  organized 
connective  tissue  as  in  osteomalacia.  Microscopically  the  relative  amount 
of  lime  appears  to  be  normal.  Fibrous  metaplasia  is  present  in  the  marrow 
and  the  medullary  canal  is  often  dilated.     Cysts  are  not  seen. 

This  process  in  the  bones  is  interpreted  by  Niklas^^  as-  "concentric 
atrophy  caused  by  lack  of  bone  apposition  where  the  resorption  is  normal," 
by  von  Lobstein^'^  as  "inertia  of  function  as  regards  bone  growth,"  by 
Frangenheim^  as  "faulty  bone  formation,"  by  Looser^^  as  "faulty  bone 
apposition  or  high  grade  atrophy  and  faulty  thickness  growth,"  by  Fuchs^" 
as  "high  grade  periosteal  dystrophy."  The  internal  organs,  central  nervous 
system  and  endocrine  glands  are  always  without  significant  changes. 

Symptoms 

The  general  symptoms  are  few.  and  seldom  striking,  in  fact  there  are 
no  characteristic  constitutional  symptoms.  Until  the  disease  is  advanced, 
i.e.,  until  multiple  fractures  have  occurred,  even  the  deformities  are  not 
marked.  With  occasional  exceptions  the  general  health  is  good  and  the 
mentality  normal. 

The  general  appearance  of  the  patient  (Fig.  ii)  conforms  to  a  moderately 
definite  type.  The  head  appears  large  in  comparison  with  the  body  and  the 
skull  shows  but  little  ossification.  By  contrast  with  the  large  skull  the 
face  is  small  but  otherwise  normal.  The  neck  is  short.  The  thorax  is 
small  though  symmetrical  and  deformed  only  as  a  result  of  the  rib  frac- 
tures. A  variable  degree  of  protrusion  of  the  abdomen  is  present.  All 
of  the  extremities  are  small,  delicate,  short  and  show  all  degrees  of  de- 
formity in  accordance  with  the  number  of  fractures.  Throughout  the 
body  the  skin  is  very  delicate,  somewhat  pale  and  in  many  places  thrown 
into  folds.  There  is  often  a  demonstrable  increase  in  the  subcutaneous 
tissues.     The  hair  is  abundant  and   silky.     Profuse   general   sweating  has 


458  OSTEOPSATHYROSIS 

been  noted  (Segawa^^).  Such  changes  are  less  marked  in  the  form  which 
develops  in  early  childhood.  These  infants  appear  normal  at  birth  but  at 
the  end  of  the  first  or  second  year  first  show  fractures  and  subsequently 
secondary  deformities  of  the  arms  and  legs.  Widespread  muscular  atrophy 
including  the  heart  was  noted  by  von  Lobstein^'^.  Ankylosis  may  finally 
result  but  is  exceedingly  rare. 

Eddowes^  in  1900  first  described  an  azure  or  deep  blue  tint  to  the 
sclera  of  many  of  these  cases  which  he  explains  on  the  basis  of  a  "deficiency 
of  fibrous  tissue  in  the  sclerotic  coat,  whose  thinness  and  transparency 
allow  the  underlying  choroidal  pigment  to  be  seen."  This  sign  (blue 
sclerotics)  has  been  repeatedly  recorded  in  published  cases. 

Fractures 

Multiple  factures  of  various  kinds  form  the  constant  and  most  char- 
■  acteristic  symptom.  An  extreme  degree  of  brittleness  in  the  bones  as 
indicated  by  the  number  of  fractures  is  present.  The  fractures  are  singu- 
larly bilateral.  A  single  case  of  true  osteogenesis  imperfecta  affecting 
the  bones'  of  only  one  side  of  the  body  has  been  reported  by  Adams^. 
Fractures  are  confined  almost  strictly  to  the  long  bones  of  the  extremities 
and  ribs,  although  the  bones  of  the  shoulder  girdle  may  occasionally  show 
the  same  lesions.  The  single  bone  most  commonly  affected  is  the  femur. 
Among  the  various  accidents  to  the  bones  an  actual  complete  transverse 
fracture  is  the  most  frequent.  In  a  few  cases  a  new  break  has  occurred 
at  the  point  of  an  old  one.  The  local  reaction  of  pain,  swelling,  tender- 
ness and  muscular  spasm  common  to  fractures  is  absent  or  insignificant. 
Crepitus  is  less  evident  than  in  fractures  of  normal  bones.  Deformities 
result  precisely  as  in  normal  fractures  from  healing  with  the  fragments 
in  bad  position.  The  amount  of  callus  formation  is  very  variable  in  size 
but  in  most  instances  it  is  probably  deficient.  Where  the  callus  is  normal, 
union  takes  place  promptly.  Kienbcck^^  emphasizes  the  slow  and  incom- 
plete healing  as  particularly  characteristic  of  the  disease.  The  cause  of 
the  fracture  is  usually  some  form  of  slight,  indirect  violence.  Some  appear 
to  be  actually  spontaneous.  So  exquisite  is  the  fragility  of  the  bones  that 
even  the  most  careful  handling  of  the  child  may  produce  one  or  more 
fractures.  Paralysis,  incoordination,  areas  of  analgesia,  and  anesthesia 
and   nystagmus  have  been  described   (Biggs^,   Segawa^^,   Hess^"*). 

X-Ray  Findings 

The  characteristics  of  the  bones  as  shown  in  roentgenograms  are  dis- 
tinctive and  of  the  first  importance  in  differential  diagnosis.     The  main 


SYMPTOMS 


459 


features  in  a  well  developed  stage  of  the  disease  may  be  summarized  as 
follows  (Lovett  and  Nichols^^  MixselPS  Biggs^  Bamberg  and  Huldschinsky^, 
Kienbock^^,  Blaine^,  Niklas^^,  Hess^^):  (i)  a  high  degree  of  osteoporosis 
uniformly  affecting  the  entire  skeleton,  the  variations  in  density  giving 
a  mottled  appearance;  (2)  marked  deformities  of  the  long  bones  of  the 
extremities  usually  of  an  angular  type  and  due  to  evident  fractures,  rarely 
also  some  actual  bowing;  (3)  apparently  normal  size  and  shape  of  bones 
except  as  altered  by  fractures  and  resulting  callus  formation;  (4)  often 
excessive  callus  formation  with  variable  degree  of  calcification.  A  trans- 
verse area  of  decalcification  is  often  seen  at  the  point  of  previous  fracture; 
(5)  the  epiphyseal  line  is  straight,  cartilage  often  thin;  (6)  a  very  faint 
shadow  is  given  by  all  bones,  frequently  scarcely  more  dense  than  the 
surrounding  soft  parts;  (7)  the  cortex  is  thin,  irregular  and  deficient  in 
lime  salts;  (8)  the  spongiosa  of  both  epiphysis  and  diaphysis  is  extremely 
faint  with  entire  absence  of  all  normal  markings;  (9)  the  medullary  cavity 
is  very  irregular  in  outline  and  dilated. 

Metabolism 

Bamberg  and  Huldschinsky^  studied  the  metabolism  in  an  infant  with 
osteogenesis  imperfecta  and  found  a  definite  nitrogen  retention  as  well 
as  a  diminished  daily  excretion  of  phosphorus  in  the  urine  and  feces. 
In  the  case  of  both  nitrogen  and  phosphorus  the  excretion  was  markedly 
increased  by  the  administration  of  phosphorus  and  cod  liver  oil.  During 
the  first  ten  day  period  of  their  experiment  there  was  a  negative  balance 
in  the  lime  which  in  later  periods  showed  a  positive  balance.  The  excretion 
of  lime  was  also  favorably  influenced  by  the  phosphorus  cod  liver  oil  prep- 
aration. Schwarz  and  Bass^''  did  similar  experiments  in  a  case  of  the 
congenital  type  and  found  the  "nitrogen  metabolism  approximately  normal 
and  the  fat  retention  and  absorption  normal."  There  was  a  positive  cal- 
cium balance  though  somewhat  below  normal,  i.e.,  109  mg.  as  against 
a  normal  of  120  to  210  mg.  The  metabolism  of  magnesium  and  phosphorus 
was  within  normal  limits.  Sodium  and  potassium  both  showed  a  positive 
balance  but  the  significance  of  the  retention  is  unknown.  In  Bookman's 
two  cases  the  phosphorus  retention  was  considerably  increased  above  the 
normal  while  the  magnesium  retention  was  low.  His  conclusions  respect- 
ing the  calcium  metabolism  in  osteogenesis  imperfecta  are:  "(i)  In  active 
cases  the  calcium  retention  is  somewhat  below  or  very  decidedly  below 
the  normal;  (2)  It  is  probable  that  variations  in  the  course  of  the  disease 
cause  a  change  in  the  calcium  balance;  (3)  The  deficient  retention  of  cal- 
cium is  apparently  influenced  favorably  by  cod  liver  oil  and  phosphorus 
and  still  more  strongly  by  calcium  lactate." 


46o  OSTEOPSATHYROSIS 


Course  and  Prognosis 

The  prognosis  varies  somewhat  with  the  different  types  of  the  disease 
and  the  intensity  of  the  process  but  is  on  the  whole  bad.  In  the  early 
form  the  mortality  is  nearly  lOO  per  cent.  (Bamberg  and  Huldschinsky) , 
the  majority  dying  in  utero  and  the  remainder  soon  after  birth.  Nathans- 
takes  exception  to  this  opinion  and  presents  evidence  to  show  that  the 
disease  is  much  less  fatal  than  usually  claimed.  It  is  said  that  these  in- 
fants are  more  susceptible  to  secondary  infections,  especially  broncho- 
pneumonia and  frequently  succumb  to  such  complications.  The  later  the 
symptoms  appear  the  better  the  chances  of  recovery.  The  usual  course 
in  those  who  survive  is  a  gradually  increasing  deformity  of  the  legs  with 
successive  fractures  during  the  first  few  years  of  life.  Subsequently  the 
child  may  learn  to  walk  and  enjoy  good  general  health.  The  fractures 
tend  to  become  less  and  less  as  the  patient  approaches  adult  life.  Ost- 
heimer^^  collected  193  cases  from  the  literature  and  found  that  in  76.5 
per  cent,  the  last  fracture  occurred  before  the  twenty-second  year,  yet 
fractures  are  recorded  as  late  as  thirty-three,  thirty-eight  and  forty-one 
years. 

Regarding  the  Irregular  course  Kienbock^^  says,  "The  affection  may 
undergo  repeated  florid  stages  and  involutions  during  the  whole  period 
of  its  existence,  thus  showing  irregular  fluctuations;  and  there  may  be 
recurrences  many  years  after  apparent  cures." 


Diagnosis 

Osteogenesis  imperfecta  of  the  congenital  type  and  in  its  typical  form 
with  multiple  fractures  offers  no  resemblance  to  any  other  disease  seen 
in  this  period  of  life.  No  other  congenital  disease  shows  general  bone 
fragility.  Neither  is  there  any  difficulty  in  differentiating  the  disease 
from  other  affections  in  infants  and  older  children  with  which  it  is  some- 
times confused.  The  numerous  fractures  following  slight  trauma  or  occur- 
ring spontaneously  and  the  characteristic  X-ray  appearances  described 
above  should  leave  no  question  of  the  nature  of  the  condition. 

The  superficial  resemblance  of  osteopsathyrosis  to  achondroplasia  is 
sometimes  confusing  and  the  relationship  between  the  two  is  probably  a 
fairly  close  one.  They  are  readily  differentiated,  however,  as  the  similarity 
in  appearance  is  confined  entirely  to  the  outward  changes  in  the  skin  and 
subcutaneous  tissue.  But  even  these  alterations  are  much  less  marked 
in  osteopsathyrosis.     The  two  conditions  are  the  exact  opposites  from  the 


TREATMENT  461 

point  of  view  of  the  nature  of  the  disease  process,  viz.,  achondroplasia  results 
from  a  distorted  function  of  the  enchondrial  ossification  process  while  in 
osteogenesis  imperfecta  the  normal  function  of  the  periosteum  and  osteo- 
blastic cells  fails  (Sumita^",  Porak  and  Durante^").  The  very  short  legs, 
the  result  of  retarded  growth,  which  are  so  characteristic  of  achondroplasia 
are  never  seen  in  osteopsathyrosis  except  as  they  may  be  somewhat  short- 
ened in  consequence  of  fractures  and  bowing.  The  tubular  bones  in  achon- 
droplasia are  short,  plump  and  sclerotic.  Moderate  bowing  may  be  present 
but  fractures  do  not  occur.  X-ray  examination  not  only  brings  out  these 
differences  in  the  forms  of  the  bones  in  the  two  diseases  but  in  the  finer 
structure  as  well.  In  achondroplasia,  furthermore,  the  process  is  prominent 
in  the  base  of  the  skull,  vertebrae  and  pelvis.  Ossification  is  complete 
in  the  skull  and  the  sutures  are  normal  or  prematurely  synostosed.  Finally, 
the  patient  with  increasing  years  remains  a  dwarf. 

Fractures  may  very  rarely  occur  in  rickets  and  congenital  syphilis 
but  there  seems  no  excuse  for  confusing  either  condition  with  osteogenesis 
imperfecta.  Rickets  is  never  congenital.  Fractures  when  present  are 
only  one  or  two  in  number  and  the  result  of  considerable  violence.  The 
fractures  are  not  intraperiosteal  as  in  osteogenesis  imperfecta  and  the  callus 
formation  is  very  slight.  Both  clinically  and  anatomically  the  two  pro- 
cesses are  absolutely  different.  X-ray  appearances  are  equally  distinct. 
In  neither  the  congenital  nor  the  later  form  of  syphilis  in  childhood  is 
there  any  resemblance  to  osteogenesis.  In  the  first  form  the  lesion  is 
primarily  an  osteochondritis  while  in  the  later  the  cortex  of  the  long  bones 
is  the  part  attacked,  the  result  being  a  thickening  or  hyperostosis  of  the 
cortex. 

Treatment 

Favorable  results  have  followed  the  administration  of  phosphorus  and 
cod  liver  oil  and  a  rational  basis  for  such  therapeusis  would  seem  to  be 
found  in  the  results  of  the  metabolism  experiments  quoted  above.  The 
following  combination  may  be  used  (Hess):  Phosphorus  o.oi  gm.  and 
cod  liver  oil  60  c.c.  or  pure  tribasic  calcium  phosphate  6  gm.  and  cod 
liver  oil  60  c.c.  The  dose  of  each  is  4  c.c.  twice  daily.  The  use  of  arsenic, 
iron,  strontium,  calcium,  thyroid,  suprarenal  and  pituitary  preparations 
has  proved  useless.  Czerny^  has  recently  reported  benefit  from  the  use 
of  raw  carrot  juice  (100  grams  daily).  He  bases  his  method  on  the  theory 
that  osteopsathyrosis  is  an  avitaminosis  and  that  the  improvement  in  his 
cases  was  due  to  the  vitamins  of  the  carrot. 

Prophylactic  treatment  designed  to  prevent-  fractures  is  important. 
As  a  special  method  of  protection  some  have  advised  the  use  of  braces  in 


462  OSTEOMALACIA 

the  most  severe  cases.  When  fractures  occur  they  should  be  treated  hke 
any  fracture,  great  care  being  exercised  that  the  fragments  are  in  good 
position  in  order  so  far  as  possible  to  prevent  the  usual  deformities.  A 
careful  hygienic-dietetic-regimen  should  be  carried  out  in  all  cases.  Mas- 
sage is  indicated  for  the  muscular  atrophy. 


Part  V 
OSTEOMALACIA 

Introduction 

Definition. — An  acquired  disease  of  a  chronic  progressive  type,  usually 
seen  in  adult  females,  appearing  in  several  forms  and  with  varied  clinical 
manifestations  but  characterized  especially  by  general  muscular  weakness 
and  pain  referred  to  the  bones.  Pathologically  the  essential  lesions  are  in 
the  skeleton  and  consist  primarily  in  a  widespread  softening  and  absorption 
of  preexisting  bone  (halisteresis)  and  the  formation  of  uncalcified  new 
osteoid  tissue.  The  process  leads  to  marked  deformities  through  bending 
and  fractures. 

The  lesions  in  the  bones  which  are  seen  in  osteomalacia  are  found  in 
many  of  the  other  diseases  of  the  bones  such  as  rickets,  osteitis  fibrosa, 
osteitis  deformans,  osteopsathyrosis  and  neoplasm,  various  diseases  of  the 
central  nervous  system  (tabes  dorsalis,  syringomyelia,  chronic  myelitis 
and  tumors),  and  by  many  authors  the  condition  is  considered  a  syndrome 
rather  than  a  distinct  and  well  defined  disease.  Bernard^,  for  example,  says, 
"one  cannot  consider  osteomalacia  a  morbid  entity,  due  to  a  sole  and 
constant  cause."  It  is  rather  "an  anatomical  clinical  syndrome,  corre- 
sponding to  the  osseous  decalcification."  He  considers  that  osteomalacia 
and  rickets  represent  the  same  syndrome  with  varying  degrees  of  intensity 
and  different  localizations,  but  possessing  the  same  "anatomic  substratum," 
i.e.,  decalcification  combined  with  reaction  on  the  part  of  the  osteogenic 
elements  of  the  bone  marrow.  In  several  of  the  above  named  diseases, 
rickets,  osteitis  fibrosa  and  osteitis  deformans,  the  absorption  of  old  bone 
and  deposit  of  osteoid  tissue  poor  in  lime  salts  are  prominent  features  and 
they  undoubtedly  bear  a  close  relation  to  osteomalacia.  Some  writers  have 
even  considered  them  as  varieties  of  a  single  disease. 

Occurrence  and  Geographical  Distribution. — In  the  United  States  the 
disease  is  among  the  most  rare  of  the  bone  affections  and  the  literature 
contains  but  few  examples.     It  is  much  more  common  in  Italy,  Germany, 


CLINICAL  VARIETIES  463 

Switzerland,  France  and  India.  As  in  the  case  of  goiter,  osteomalacia  is 
very  frequently  met  with  in  certain  limited  districts,  as  the  Ergolzthal  in 
Switzerland  and  several  of  the  districts  in  northern  India.  In  England  and 
other  countries  the  disease  is  seldom  seen  and  in  Japan  is  practically  un- 
known. A  few  observations  indicate  that  in  some  countries  it  is  most 
prevalent  along  river  valleys.  Osteomalacia  is  known  to  occur  in  the  lower 
animals,  especially  in  cattle  and  sheep. 


Clinical  Varieties 

Many  attempts  have  been  made  to  divide  the  cases  into  separate  groups 
but  without  complete  success.  The  disease  as  observed  at  different  ages 
and  during  pregnancy  shows  no  essential  clinical  differences  but  in  a  general 
way  it  is  possible  to  classify  cases  according  to  the  period  of  life  when  it 
appears  and  with  reference  to  pregnancy. 

Puerperal  Form. — By  far  the  vast  majority  of  cases  occur  in  pregnant 
women  or  during  the  period  of  lactation. 

Non-puerperal  Form. — The  clinical  features  and  pathological  changes 
seen  in  the  non-pregnant  women  and  in  men  do  not  differ  from  the  above 
except  that  they  are  usually  much  less  severe  and  the  process  is  less  pre- 
dominant in  the  pelvis  and  more  widespread.  The  non-puerperal  form  is 
also  less  apt  to  show  remissions  and  exacerbations.  Males  seem  to  be  as 
frequently  attacked  as  females  in  this  form. 

Juvenile  Osteomalacia. — Much  confusion  exists  regarding  the  disease  in 
children  and  some  doubt  its  existence  in  the  early  years  of  life.  Undoubtedly 
some  of  the  reported  cases  were  confused  with  rickets,  but  a  sufficient  number 
of  examples  of  true  osteomalacia  have  been  reported  by  careful  observers  to 
establish  the  fact  that  the  disease  may  occur  at  the  time  of  adolescence 
(Fig.  13).  Zesas^'^  states  that  osteomalacia  does  occur  during  the  first  few 
years  of  life  mainly  following  trauma,  bronchopneumonia  and  the  infections. 

Senile  Osteomalacia. — The  considerable  number  of  cases  of  osteomalacia 
in  individuals  past  middle  life  reported  during  the  past  twenty  years  indi- 
cates that  the  senile  form  is  not  so  rare  as  formerly  believed.  The  onset  is 
more  gradual,  although  it  is  sometimes  sudden,  the  course  often  prolonged 
and  the  symptoms  less  severe.  Schiffmacher^^  says,  "in  the  beginning  of  the 
senile  period  osteomalacias  may  appear,  the  symptoms  of  which  are  not  all 
identical  with  those  of  puerperal  osteomalacia  and  which  must  be  carefully 
differentiated  from  the  ordinary  osteoporosis."  Drasche^  mentions  the 
chief  distinguishing  clinical  feature  which  separates  it  from  osteoporosis  as 
the  flexibility.  Like  the  juvenile  form  the  alterations  in  the  pelvis  are  not  so 
prominent.    Complications  by  conditions  common  to  old  age  and  especially 


464  OSTEOMALACIA 

those   associated   with    arteriosclerosis    may   obscure    the    picture   of    the 
osteomalacia. 

Zesas^°  speaks  of  still  another  form  due  to  diseases  of  the  central  nervous 
system  (tabes,  syringomyelia,  chronic  myelitis  and  tumors)  which  he  calls 
"neurotic  malacia"  and  which  he  explains  as  "trophoneurotic  disturbances 
of  the  nutrition  of  the. bones." 

Etiology 

There  is  no  good  evidence  that  heredity  is  of  any  importance  etiologlcally. 

Age. — Osteomalacia  is  primarily  a  disease  of  early  adult  life,  in  the 
majority  of  cases  the  first  symptoms  appearing  between  the  twentieth  and 
thirtieth  years.  Scott^'''  found  the  average  of  cases  in  India  to  be  20.7  years. 
A  few  typical  examples  of  the  disease  have  been  reported  in  individuals  under 
twenty,  chiefly  at  the  time  of  adolescence  and  most  authors  now  recognize 
a  juvenile  form.  Its  occurrence  in  infancy  is  still  a  matter  of  dispute.  The 
incidence  of  osteomalacia  after  thirty  is  much  greater  than  under  twenty 
years.  Zesas^'*  quotes  figures  on  this  point.  Among  247  cases,  twenty-two, 
or  nine  per  .cent.,  were  over  forty- five  years  of  age.  Even  extreme  old  age  is 
not  exempt. 

Sex. — The  overwhelming  majority  of  cases  occur  in  women.  Only 
thirty-nine  of  a  total  of  360  cases  collected  by  McCrudden^^  were  in  men. 
Scott  gives  the  ratio  of  males  to  females  in  India  as  i  :50. 

Pregnancy. — The  close  relation  between  osteomalacia  and  pregnancy  and 
lactation  is  unmistakable  but  the  precise  part  played  etiologlcally  by  these 
conditions  is  a  matter  of  much  difference  of  opinion.  Guthrie^  quotes 
Sitzmann  and  Durham  as  having  collected  132  cases  of  osteomalacia  of 
which  91  were  associated  with  pregnancy.  The  disease  seldom  develops 
in  primiparae  and  seems  to  be  more  prevalent  among  women  with  very 
frequent  pregnancies.  The  average  number  of  pregnancies  in  the  cases 
studied  by  Scott  was  3.8,  and  the  same  author  gives  the  figures  for  Italian 
cases  as  five.  It  is  a  common  clinical  observation  that  the  disease  first 
appears  in  a  mild  form  and  frequently  seems  to  disappear  after  lactation  is 
finished  but  reappears  in  a  more  severe  form  with  each  succeeding  pregnancy. 

A  bewildering  number  of  theories  as  to  the  cause  of  the  disease  have  been 
advanced  but  the  majority  are  based  on  mere  clinical  and  often  inaccurate 
observations.  It  is  only  within  very  recent  years  that  the  chemical  studies 
of  various  authors,  and  especially  the  brilliant  work  of  McCrudden,  have 
thrown  some  light  on  the  problem. 

I.  Such  general  factors  as  environment,  general  hygiene,  social  status, 
general  habits  of  life  and  diet  have  often  been  mentioned  as  possible  causes 
of  osteomalacia.     Statistics  show  that  the  disease  is  very  definitely  more 


Fig.    13. — Osteomalacia.      Skeleton    of    adult, 
(Warren  Museum,  Harvard  Medical  School.) 


Facing  464 


ETIOLOGY  465 

common  among  the  poorer  classes  and  those  who  live  under  unhygienic 
surroundings  but  it  is  also  found  among  the  well-to-do.  The  prevalence  of 
the  disease  in  certain  limited  localities  also  suggests  the  possible  influence 
of  some  of  the  above  factors.  Similar  evidence  exists  in  the  case  of  cattle. 
Osteomalacia,  for  example,  is  endemic  in  the  region  of  Augsburg  where  the 
soil  is  found  to  contain  fifty  to  sixty  per  cent,  of  pure  carbonate  of  lime  but 
is  poor  in  phosphoric  acid  and  the  fodder  is  markedly  deficient  in  calcium 
phosphate  (Zesas).  Numerous  feeding  experiments  in  animals  of  various 
species  have  shown  that  osteomalacia  can  be  produced  by  prolonged  feeding 
with  a  calcium-free  diet.  A  very  careful  study  of  diet  as  a  possible  etiological 
factor  in  cases  occurring  in  India  was  made  by  Scott^^  and  with  negative 
results.  The  application  of  these  observations  is,  however,  a  very  limited  one 
and  any  role  which  they  may  play  in  causing  osteomalacia  through  faulty 
nutrition  must  be  a  very  minor  one. 

2.  One  of  the  oldest  hypotheses  is  that  the  process  of  absorption  in  the 
bones  is  the  result  of  the  action  of  some  acid  contained  in  the  blood  or  tissues 
which  dissolves  out  the  mineral  constituents.  Lactic,  oxalic,  acetic,  formic 
and  carbonic  acids  have  in  turn  been  suggested.  For  many  obvious  reasons 
this  theory  is  absurd  and  mention  is  made  of  it  only  because  of  the  promin- 
ence which  has  been  given  it  in  the  literature  of  osteomalacia. 

3.  The  course  of  the  disease,  the  nature  of  the  changes  in  the  bones  and 
the  fact  that  it  is  known  to  follow  such  infections  as  scarlet  fever,  pneumonia, 
rheumatic  fever,  influenza,  syphilis  and  typhoid  have  suggested  that  the 
disease  itself  may  be  caused  by  some  specific  organism  with  or  without 
antecedent  trauma.  Many  authors  regard  the  disease  as  probably  an 
infection  and  the  softening  in  the  bones,  the  result  of  the  presence  of  micro- 
organisms or  their  toxins.  Petrone^"  in  1892  claimed  to  have  isolated  an 
organism  ("micrococcus  nitrificans")  which  when  injected  into  dogs  caused 
bone  changes  characteristic  of  osteomalacia.  Arcangeli^  in  1902  and  1907, 
made  similar  claims  for  a  microorganism  which  he  named  "diplococcus 
osteomalacia  hominis."  He  reports  a  cure  in  thirteen  cases  by  the  use  of 
vaccines  prepared  from  this  diplococcus.  The  work  of  these  authors  has 
not  been  verified  and  the  theory  finds  no  support  either  in  the  clinical  facts 
or  the  post-mortem  studies. 

4.  Much  evidence  points  to  the  cause  of  the  disease  in  some  disturbance 
of  function  in  the  glands  of  internal  secretion  (ovary,  suprarenals,  thyroid, 
parathyroid  and  hypophysis)  which  directly  or  indirectly  affects  the 
metabolism  in  the  bones.  Hoennicke^^  considers  that  the  disease  is  the 
result  of  disturbed  function  of  the  thyroid.  He  has  observed  one  case  and 
quotes  several  others  showing  an  association  of  exophthalmic  goiter  and 
osteomalacia  in  the  same  individual.  In  certain  localities  where  Graves' 
disease  is  prevalent,   osteomalacia   is   also   common.      In   other   instances 

Vol.  IV.  30 


466  OSTEOMALACIA 

thyroid  symptoms  may  appear  in  the  course  of  osteomalacia.  Atrophy  of 
the  thyroid  is  known  to  lead  to  limitations  in  length  and  growth  of  bones,  a 
consideration  to  which  Hoennicke  attaches  much  importance.  This  author 
states  that  the  thyroid  gland  shows  an  abnormal  structure  in  most  cases  of 
osteomalacia  but  pathological  reports  do  not  bear  out  this  statement.  He 
finds  evidence  for  the  probable  association  of  the  thyroid  and  ovary  in 
producing  the  bone  lesions,  i.e.,  the  diseased  thyroid  inducing  an  increase 
in  the  excretion  of  phosphorus  which  is  aggravated  by  hyperactivity  of  the 
ovaries  and  especially  during  pregnancy.  The  evidence  which  Hoennicke 
offers  as  proof  of  his  theory  is  by  no  means  sufficient  and  the  theory  has 
received  but  little  support. 

The  publication  of  favorable  results  in  osteomalacia  from  the  adminis- 
tration of  adrenalin  by  Bossi^  in  1907  seemed  to  offer  excellent  evidence  of  a 
probable  cause  of  the  disease  in  a  deficiency  in  the  suprarenal  glands.  This 
probability  might  seem  further  emphasized  by  the  known  influence  of  the 
secretion  of  the  suprarenals  on  the  ovarian  activity  and  the  general  belief 
that  the  adrenal  secretion  influences  bone  metabolism.  It  seems  fair  to  say 
that  the  theory  of  the  dependence  of  the  marked  disturbance  in  the  bone 
metabolism  in  osteomalacia  on  alterations  in  these  glands  rests  on  no  firmer 
basis  than  the  evidence  of  empirical  treatment. 

Of  all  the  endocrine  glands  the  ovary  would  seem  to  stand  out  as  the  one 
most  probably  concerned  in  the  morbid  process  in  osteomalacia.  The 
occurrence  of  the  disease  in  the  great  majority  of  cases  in  women  during 
pregnancy,  the  "physiological  osteomalacia"  of  Hanau^°,  which  is  known  to 
occur  in  many  normal  women  during  the  later  months  of  pregnancy  and  the 
supposed  striking  improvement  following  removal  of  the  ovaries  in  osteo- 
malacia all  point  strongly  to  this  organ  as  concerned  in  the  etiology.  Fochier^ 
in  1879  when  performing  a  Caesarean  section  on  a  case  of  osteomalacia 
removed  the  uterus  and  ovaries.  The  case  recovered  from  the  osteomalacia 
and  on  the  basis  of  this  experience  Fochier  recommended  the  oophorectomy 
for  the  cure  of  osteomalacia,  his  theory  being  that  the  disease  is  due  to  a 
hyperactivity  of  the  ovaries.  Fehling'^  in  1894  reported  the  first  series 
of  cases  treated  by  this  method  and  claimed  extraordinarily  favorable 
results.  McCrudden*^'  ^^  has  made  a  very  exhaustive  and  scientific  investi- 
gation of  the  relation  of  the  ovaries  to  osteomalacia.  His  numerous  experi- 
ments on  animals  establish  the  important  fact  that  castration  has  no  effect 
on  the  general  metabolism.  A  case^on  whom  castration  was  done  was 
studied  before  the  operation,  a  few  months  later,  and  a  year  subsequently. 
The  removal  had  no  beneficial  effects  on  the  osteomalacia  gnd  the  metab- 
olism was  unchanged.  McCrudden^^  further  made  a  critical  study  of  the 
cases  reported  in  the  literature  treated  by  oophorectomy  and  found  but  a 
small  percentage  with  evidence  of  cure.     He  very  reasonably  raises  the 


ETIOLOGY  .467 

question,  "if  osteomalacia  is  due  to  overactivity  of  the  ovaries,  it  is  difificult 
to  understand  how  a  patient  without  ovaries  can  have  osteomalacia."  The 
importance  of  castration  in  these  cases  is,  as  McCrudden  suggests,  that  it 
prevents  further  conceptions  which  are  so  apt  to  be  accompanied  by  severe 
exacerbations  of  the  disease.  This  appears  to  be  sufficient  proof,  as 
McCrudden  contends,  that  "osteomalacia  is  not  a  disease  of  the  ovaries." 

McCrudden ^^'^^  has  worked  out  a  complete  explanation  of  the  bone 
changes  in  osteomalacia  which  in  every  respect  is  consistent  with  the  known 
facts  regarding  the  disease  and  which,  it  seems  probable,  will  find  general 
acceptance.  This  author  finds  abundant  proof  in  the  chemical  and  patho- 
logical studies  made  of  Cohnheim's  conception  of  bone  as  a  living  tissue 
which  undergoes  anabolism  and  catabolism  like  an}^  other  living  tissue. 
When  this  interpretation  is  applied  to  the  process  in  osteomalacia  we  see  not 
a  simple  halisteresis  of  bone  as  claimed  by  Virchow  and  others  but  absorption 
of  old  bone  plus  an  active  anabolism  in  the  formation  of  new  osteoid  tissue 
poor  in  lime  salts.  The  laying  down  of  new  osteoid  tissue  is  entirely  in 
accord  with  the  repeated  demonstration  of  the  retention  of  sulphur  and 
magnesium  in  relatively  greater  amounts  than  the  nitrogen  as  the  tissue 
formed  is  unusually  rich  in  these  two  elements.  As  this  new  bone  is  very 
poor  in  lime  and  as  the  old  bone  is  being  rapidly  decalcified  and  absorbed 
there  is  an  increased  excretion  of  calcium.  In  osteomalacia  there  is  evidently 
a  more  or  less  severe  disturbance  of  the  normal  balance  of  the  anabolic  and 
catabolic  processes  in  the  bones.  How  this  disturbance  comes  about  is  the 
key  to  the  etiology.  The  osseous  system  may  be  regarded  as  a  storehouse  of 
lime.  During  pregnancy  there  is  a  greatly  increased  need  for  calcium  to 
meet  the  demands  of  the  developing  bones  of  the  fetus  and  this  call  is  met 
by  the  increased  catabolism  of  the  maternal  bones.  It  is  important  at  this 
point  to  recall  the  results  obtained  by  Hanau^",  namely,  that  the  bones  of 
apparently  healthy  pregnant  women  are  often  deficient  in  lime  salts,  i.e., 
changes  similar  to  those  found  in  osteomalacia  but  less  severe  have  taken 
place,  a  "physiological  osteomalacia"  so-called.  The  chemical  analysis  of  the 
bones  and  the  study  of  the  metabolism  in  osteomalacia  give  results  in  support 
of  this.  The  bones  are  relatively  poor  in  mineral  constituents,  especially 
phosphate  of  lime,  and  relatively  rich  in  organic  matter.  Metabolism 
studies  show  an  increased  excretion  of  calcium  and  a  retention  of  sulphur 
and  magnesium.  During  the  early  stages  of  puerperal  osteomalacia  there  is 
an  actual  retention  of  calcium.  McCrudden  has  shown  that  to  a  certain 
degree  the  calcium  phosphate  is  replaced  by  magnesium  phosphate. 

A  further  observation  forms  another  important  link.  Osteomalacia 
rarely  begins  until  after  the  second  or  third  pregnancy  and  then  as  a  rule  in 
women  of  poor  general  nutrition  and  whose  environment  is  unhygienic.  The 
patient  often  recovers  from  the  first  attacks  but  suffers  a  remission  with  the 


468  OSTEOMALACIA 

next  pregnancy,  the  condition  becoming  exaggerated  with  each  succeeding 
one.  "In  other  words,  it  is  only  after  a  long  continued  and  severe  drain  on 
the  bones  of  a  poorly  nourished  patient  that  the  body  fails  to  respond  to  the 
demands  on  it  and  even  then  recovery  follows  if  the  severe  demands  are  not 
continued.  .  .  .  After  repeated,  rapidly  following  pregnancies,  the 
amount  of  calcium  phosphate  in  the  bones  becomes  less  and  less.  A  new 
pregnancy  begins  before  the  organism  has  made  up  for  the  loss  of  calcium 
phosphate  in  the  preceding  pregnancy.  .  .  .  The  condition  of  greatest 
importance  would  seem  to  be  a  marked  tendency  to  overprolongation  of  the 
period  of  calcium  flux"  (McCrudden). 

The  cause  of  the  disease  in  the  non-puerperal  form  is  somewhat  less 
clear.  McCrudden^^'  ^^  cites  the  calcification  of  various  tissues  (dura,  pia, 
choroid,  muscles,  bladder,  lungs,  pleura,  stomach,  liver  and  lymph  nodes) 
and  the  heteroplastic  bone  formation  occasionally  observed  and  argues  that 
some  such  prolonged  demand  for  calcium  increases  the  catabolism  in  the 
skeleton  and  upsets  the  metabolism  balance.  He  suggests  the  possibility  that 
the  process  once  started  may  continue  after  the  primary  need  has  ceased. 


Pathology 

The  affected  bones  in  osteomalacia  are  abnormally  soft,  pliable,  friable, 
easily  cut  with  a  knife,  and  consequently  deformities  and  fractures  are 
common.  As  the  process  in  the  individual  bones  proceeds  unequally  the 
deformities  may  comprise  the  entire  bone  or  only  a  portion.  In  the  long 
bones  particularly,  bowing  of  an  irregular,  angular  type  is  very  characteristic 
but  in  sharp  contrast  to  the  even  broad  curves  seen  in  osteitis  deformans 
(Fig..  13).  As  a  result  of  the  extensive  decalcification  and  absorption  the 
diseased  bone  is  much  lighter  than  normal  bone. 

In  the  puerperal  form  the  pelvis  is  the  part  of  the  skeleton  most  fre- 
quently attacked  but  in  the  majority  of  cases  the  spine  is  also  involved.  The 
bones  of  the  thorax  stand  next  in  order  followed  by  the  long  bones  of  the 
extremities.  Involvement  of  the  skull  is  rare.  In  the  non-puerperal  form 
the  pelvis,  spine,  ribs  and  the  long  bones  of  the  extremities  are  affected  with 
about  the  same  degree  of  frequency.  The  skull  not  infrequently  participates. 
The  characteristics  of  the  deformities  in  the  individual  bones  are  important 
as  they  are  for  the  most  part  unlike  those  seen  in  any  other  disease.  The 
pelvis  shows  the  greatest  change  in  form.  The  sacrum  under  the  weight  of 
the  body  is  forced  downward  while  the  pelvis  is  compressed  laterally  forcing 
the  symphysis  forward  to  form  a  sharp  angle.  The  outlet  of  the  pelvis  is  in 
consequence  greatly  contracted  and  to  greater  extent  than  the  inlet,  yet  in 
spite  of  this  the  bones  are  so  pliable  that  normal  delivery  may  take  place. 


PATHOLOGY  469 

The  form  of  the  pelvis  is  often  spoken  of  as  heart  shaped  or  cloverleaf  in 
form.  To  a  considerable  degree  the  ultimate  form  of  the  pelvis  depends  on 
the  position  assumed  for  a  long  period  while  the  patient  is  confined  in  bed. 
Marked  and  extensive  changes  in  the  spine  are  particularly  common.  The 
individual  vertebrae  are  compressed,  misshapen  and  displaced;  hence  a 
considerable  shortening  of  the  vertebral  column.  There  is  a  combination 
of  lateral  curvature  with  an  accentuation  of  the  normal  curves  which  is 
sometimes  extreme.  The  changes  in  the  thorax  do  not  conform  to  any 
definite  type.  Through  bending  of  the  spine,  clavicles  and  sternum,  as  well 
as  numerous  fractures  and  deformity  of  the  ribs,  the  whole  thorax  may  be 
greatly  distorted  and  cause  displacement  of  the  intrathoracic  organs.  Severe 
subjective  symptoms  often  result.  Involvement  of  the  extremities  though 
less  severe  and  later  in  developing  than  the  above  is  nevertheless  usually 
present  in  all  severe  cases.  The  arms  seldom  show  as  marked  alterations  as 
do  the  legs.  The  femur  and  tibia  are  most  commonly  involved.  Irregular 
and  asymmetrical  bending  with  fractures  is  seen  but  rarely  any  consider- 
able enlargement  since  callus  formation  is  practically  wanting.  The  skull  is 
sometimes  attacked  but  is  never  deformed. 

The  outer  surface  of  the  bones  is  uneven  and  in  many  places  injected.  On 
section  the  entire  structure  seems  to  be  altered,  almost  nothing  remaining  of 
the  normal  bone  architecture.  The  cut  surface  is  yellow  or  red  in  color  and  is 
generally  hyperemic  or  with  ecchymotic  areas.  The  normal  trabecular 
structure  is  nearly  wanting  while  the  marrow  spaces  are  enormously  enlarged 
and  filled  with  altered  marrow.  Small  cysts  filled  with  yellowish  or  bloody 
fluid  are  occasionally  seen.  The  cortex,  especially  in  the  long  bones,  may  be 
a  mere  thin  shell  or  entirely  absent.  The  periosteum  is  adherent,  somewhat 
thickened  and  hyperemic. 

On  microscopic  examination  the  trabeculae  are  seen  to  be  thin  and  widely 
separated.  The  central  portion  of  the  trabeculae  in  many  places  retains  the 
appearance  of  the  normal  bone  but  is  surrounded  by  the  decalcified  material. 
The  perforating  canals  are  numerous,  dilated  and  surrounded  by  the  same 
calcium  free  tissue.  Schmidt^^  interprets  the  appearances  as  indicating  that 
the  lamellae  where  crossed  by  the  perforating  canals  have  become  decalcified 
thus  leaving  an  encircling  zone  of  osteoid  tissue.  This  process  begins  in  the 
medullary  portion  of  the  bone.  The  new  osteoid  tissue,  which  is  often 
extensive,  is  formed  largely  from  the  proliferating  medullary  membrane  but 
to  some  extent  also  from  the  periosteum  (Schmidt^^,  Tashiro^^).  Osteoclasts 
are  present  in  moderate  numbers  in  the  osteoid  tissue  (von  Recklinghausen^^, 
von  Ribbert^^).  The  bone  lesions  were  formerly  interpreted  by  Virchow,  von 
Recklinghausen  and  others  as  solely  the  result  of  halisteresis  but  later 
studies  have  proved  that  much  of  the  abundant-osteoid  tissue  is  not  due  to 
this  process  but  to  the  laying  down  of  uncalcified  new  bone.    Von  Reckling- 


470  OSTEOMALACIA 

hausen^^  has  in  a  later  publication  accepted  this  view  of  the  double  origin  of 
the  osteoid  tissue.  The  marrow  appears  much  more  hyperemic  than  normal 
and  is  particularly  rich  in  cells.  Hemorrhage  into  the  bone  marrow  can  be 
seen  in  many  places.  No  constant  changes  occur  in  the  epiphyseal  cartilage. 
The  joints  remain  unchanged  at  first  but  finally  undergo  moderate 
atrophy  resulting  from  disuse.  In  the  final  stage  extensive  ankylosis  often 
forms,  the  muscles  show  general  atrophy  and  fatty  degeneration.  Various 
abnormalities  have  been  found  in  the  ovaries  and  thyroid  but  none  which 
are  constant  and  characteristic. 


Chemical  Composition  of  the  Bones  in  Osteomalacia 

In  recent  years  McCrudden^^'^'^'^^  has  made  very  exhaustive  chemical 
studies  of  the  bones  and  reviewed  the  entire  subject.  Briefly  summarized, 
the  results  of  these  bone  analyses  show  a  constant  decrease  in  the  proportion 
of  inorganic  constituents  and  a  corresponding  increase  in  the  proportion  of 
organic  constituents.  McCrudden  finds  the  increase  in  the  percentage  of 
organic  constituents  much  greater  than  can  be  accounted  for  on  the  basis 
of  decalcification  alone  and  interprets  this  fact  as  direct  and  important 
evidence  in  support  of  Cohnheim's  conception  of  bone  as  a  living  tissue. 
The  relatively  large  proportion  of  organic  constituents  can  be  accounted 
for,  in  other  words,  only  on  the  theory  that  new  osteoid  tissue  is  formed 
coincidently  with  the  decalcification  of  old  bone. 

The  figures  for  numerous  analyses  given  by  McCrudden  show  moderate 
variations  but  the  average  gives  a  loss  of  calcium  in  the  dried  bone  to 
approximately  one-half  the  normal.  Phosphate  is  decreased  also  but  to 
only  about  two-thirds  the  normal,  making  the  P205:CaO  ratio  in  osteo- 
malacia somewhat  higher  than  normal.  The  magnesium  and  sulphur  were 
more  than  four  tim.es  the  normal  and  he  explains  this  as  the  result  of  in- 
creased deposition  of  new  bone,  the  magnesium  to  supply  the  deficiency  in 
calcium  and  the  sulphur  as  a  normal  constituent  of  the  organic  matrix. 


Symptoms 

The  disease  is  scarcely  ever  recognized  until  it  has  reached  a  well  devel- 
oped or  even  a  late  stage.  This  is  perhaps  partly  due  to  the  fact  that  osteo- 
malacia is  a  rare  malady  and  its  symptoms  are  not  familiar  to  physicians 
generally.  A  more  important  reason  is  that  the  onset  is  gradual  and  irregu- 
lar. Until  the  process  in  the  bones  has  reached  the  point  where  deformities 
and  fractures  occur  or  until  sufficient  changes  have  taken  place  to  give 
typical  appearances  in  the  X-rays  a  diagnosis  is  hardly  possible. 


SYMPTOMS  471 

The  earliest  and  most  constant  symptom  is  pain  which  varies  from  a  dull 
rheumatic  type  to  intense  neuralgic.  The  common  seat  of  the  pain  is  the 
pelvis,  back,  hips,  thorax,  neck,  extremities  or  the  hip  and  knee  joints. 
These  pains  are  more  acute  at  night,  at  the  time  of  the  catamenia  and  are 
aggravated  by  movement  or  pressure  over  the  bones.  When  the  spine  is 
involved  the  patient  often  suffers  from  girdle  pains.  In  pregnant  women 
particularly  the  first  indication  of  the  disease  is  apt  to  be  constant  dull  pain 
in  the  pelvis  which  is  increased  by  walking  or  sitting  for  a  long  period  in  one 
position.  Cramps  and  spasms  of  the  muscles  may  follow  or  in  occasional 
cases  are  the  initial  symptoms.  The  muscles  of  the  leg,  especially  the 
adductors  and  flexors  of  the  hip  and  knee,  are  held  rigidly  to  prevent  move- 
ment. As  a  result  it  is  hard  to  straighten  the  legs  in  bed  and  walking  and 
climbing  stairs  become  difficult.  The  gait  is  a  peculiar,  characteristic 
shuffle  and  is  sometimes  spoken  of  as  the  duck  gait.  The  advancing  leg  is 
jerked  or  dragged  forward  without  raising  the  foot  from  the  floor,  which 
gives  a  curious  spastic  or  waddling  appearance.  Muscle  fatigue  is  easily 
induced.  Exaggeration  of  the  reflexes,  disturbances  of  sensation,  intention 
tremor  and  even  paralysis  may  accompany  the  above  symptoms.  Scott^^ 
quotes  a  case  in  whom  the  onset  took  the  form  of  a  tetanoid  attack  followed 
by  cramps  and  stiffness  in  the  legs. 

The  objective  symptoms  in  a  well  developed  case  of  osteomalacia  are  ex- 
tremely variable  depending  on  the  part  of  the  skeleton  most  involved.  De- 
formities (Figs.  13  and  I4)arestrikin^  and  appear  relatively  early  in  thecourse 
of  the  disease.  In  consequence  of  the  lordosis,  kyphosis  and  scoliosis  of  the 
spine  together  with  the  compression  of  the  pelvis  there  is  a  very  evident  dim- 
inution in  height.  The  thorax  is  distorted,  the  commonest  changes  being  a 
lateral  compression  with  resulting  increase  in  the  anteroposterior  diameter 
and  protrusion  of  the  sternum  (pigeon  breast).  The  clavicles  are  strongly 
arched.  Frequently  many  of  the  ribs  become  fractured  causing  a  local 
depression  of  the  chest.  Just  below  the  lower  limits  of  the  thorax  in  the 
lumbar  region  is  a  deep  transverse  groove  due  to  the  shortening  of  the  spine. 
The  pelvis  is  most  commonly  involved  of  all  the  bones  and  presents  a 
fairly  constant  type  of  deformity.  It  has  been  described  as  crumpled.  There 
is  both  a  downward  and  lateral  compression,  the  sacrum  being  forced  down- 
ward and  forward  and  the  iliac  bones  pressed  inward.  The  ischial  tuber- 
osities are  brought  nearer  together.  The  symphysis  pubis  protrudes 
anteriorly,  the  duck  bill  form,  so-called.  The  long  bones  of  the  legs  are  more 
affected  than  those  of  the  arms  (Fig.  13).  The  femur  and  tibia  especially 
are  irregularly  curved,  the  bowing  being  usually  forward.  Genu  valgum 
is  often  present  though  genu  extrorsum  does  occasionally  occur.  Multiple 
fractures  may  lead  to  very  great  deformities  especially  since  only  a  very 
sm^all  callus  is  usually  formed. 


472  OSTEOMALACIA 

Menstruation  is  usually  normal  and  osteomalacic  women  are  considered 
to  be  abnormally  fertile.  In  the  early  stages  parturition  is  normal  but  with 
each  succeeding  pregnancy  delivery  becomes  increasingly  difficult  and 
finally  is  possible  only  by  Caesarian  section. 

In  the  late  stage  of  the  disease  the  patient  becomes  bedridden  and  the 
deformities  reach  a  more  and  more  extreme  degree  as  the  result  of  fractures 
and  muscle  contractures.  At  this  stage  ankylosis  and  distortion  of  the 
joints  take  place.  Muscle  wasting  becomes  extreme  and  finally  severe 
cachexia  supervenes.  Functional  disturbances  follow,  bronchitis,  dyspnea, 
palpitation,  edema,  digestive  disturbances,  fever,  hyperhidrosis,  psychic 
instability  and  disturbances  of  secretion.  The  patient  looks  prematurely 
old.    Decubitus  may  develop. 

The  blood  undergoes  no  significant  changes.  Varying  degrees  of  anemia 
may  develop  in  the  severe  cases.  Eichorst^  mentions  an  increase  in  the 
myelocytes  and  eosinophils  in  occasional  cases.  Hyperleukocytosis  has  been 
present  in  a  few.  Scott^^  examined  thirty-seven  cases  with  reference  to 
the  amount  of  calcium  in  the  blood  and  concludes  that  the  calcium  content 
of  the  blood  is  increased  in  osteomalacia  but  the  rise  is  not  influenced  by 
pregnancy  or  lactation. 

Many  reports  have  been  made  of  lactic  acid  in  the  urine  but  McCrudden^^ 
condemns  the  chemical  methods  used.  He  has  never  been  able  to  demon- 
strate this  substance  in  the  urine  and  states  that  there  is  no  good  evidence 
that  lactic  acid  occurs  in  the  urine  in  osteomalacia.  Bence-Jones  albumose 
is  said  to  have  been  found  in  osteomalacia  but  it  is  probable  that  multiple 
myeloma  was  mistaken  for  this  disease.  Dock^,  however,  mentions  a  personal 
observation  of  a  typical  case  of  osteomalacia  In  which  the  urine  contained  the 
Bence-Jones  body.  Scott^^  found  an  increase  of  0.26  grams  of  calcium 
chloride  per  liter  of  urine  (i.i  grams  calcium  chloride  per  liter  being  normal) 
in  non-puerperal  osteomalacia,  and  a  deficit  (0.988  grams)  in  the  presence  of 
either  pregnancy  or  lactation.  This  deficit  is  interpreted  by  this  author  as 
indicating  that  the  calcium  is  being  withdrawn  from  the  maternal  bones 
to  meet  the  demands  of  the  growing  skeleton  of  the  fetus.  No  diagnostic  or 
prognostic  value  can  be  given  to  the  calcium  and  phosphates  excreted  in  the 
urine  as  the  amount  is  so  variable.  The  content  of  these  substances  in  the 
urine  is  often  greatly  increased  but  does  not  parallel  the  clinical  course. 


Metabolism  in  Osteomalacia 

McCrudden^^  summarizes  the  results  of  his  own  and  others'  experiments 
as  follows:  "We  find  that  the  body  is  losing  calcium  and  retaining  magne- 
sium and  sulphur.    These  results  are  in  accord  with  those  obtained  by  bone 


Fig.   14. — Osteomalacia.     Girl,  age   15. 
(Case  of  Dr.  C.  F.  Painter.) 


Facing  472 


DIAGNOSIS  473 

analyses  and  confirm  the  supposition  that  in  osteomalacia  the  process  is  not 
one  of  simple  passive  halisteresis,  but  an  active  one  of  increased  bone 
metabolism.  Old  bone  is  destroyed  and  new  bone  laid  down,  but  the  new 
bone  is  similar  to  the  organic  matrix  of  normal  bone  and  is  free  from,  or 
poor  in,  calcium  phosphate,  instead  of  which  there  is  a  partial  replacement 
of  the  calcium  phosphate  by  magnesium  phosphate." 


X-RAY 

The  X-ray  appearances  in  the  bones  are  peculiarly  distinctive  in  well 
marked  osteomalacia.  They  show  extreme  irregularity  in  the  contour  of  the 
bones  with  broad  or  angular  curves  in  the  diaphyses.  Fractures  are  often 
evident,  usually  with  only  a  poorly  formed  callus  or  rarely  none.  The  most 
striking  characteristic  is  the  extraordinary  rarefaction  of  the  bony  tissue.  It 
appears  hazy,  indistinct  and  offers  almost  no  contrast  to  the  soft  parts.  Only 
here  and  there  is  any  trabecular  structure  evident.  The  medullary  cavity  is 
dilated  and  the  cortex  very  thin.  The  epiphyses  are  generally  transparent 
but  free  from  deformities. 


Course  and  Prognosis 

The  course  of  osteomalacia  is  variable.  Most  cases  run  a  chronic  course 
extending  over  many  years.  Occasionally  periods  of  remission  lasting  for 
months  or  even  a  few  years  interrupt  the  progress  of  the  disease  but  they  are 
succeeded  by  exacerbations.  In  Scott's^''  series  the  maximum  duration  was 
thirty  years  and  the  average  6.5  years.  The  course  is  often  determined 
largely  by  the  number  of  pregnancies  and  the  duration  of  lactation.  Very 
rarely  after  the  disease  has  progressed  for  some  time  a  spontaneous  cure 
results  so  far  as  further  progress  of  the  disease  is  concerned.  Scott  observed 
two  such  cases.  Also  in  rare  instances  the  disease  runs  a  very  acute  course 
of  only  a  few  months.  Ogata^^  gives  a  general  death  rate  of  80  per  cent. 
Hellier^^  calculated  a  mortality  of  70  per  cent,  in  the  puerperal  and  84.7  per 
cent,  in  the  non-puerperal  form.  Death  may  result  from  cachexia  or  from 
cardiac  failure  or  some  intercurrent  infection. 


Diagnosis 

Osteomalacia  in  its  late  stages  presents  such  unique  deformities  that  no 
possibility  should  arise  of  confusion  with  any  other  disease.     Early  in  its 


474  OSTEOMALACIA 

course,  however,  diagnosis  is  very  often  exceedingly  difficult.  The  special 
diagnostic  features  are  the  age  period,  sex,  the  usual  occurrence  with 
pregnancy,  the  onset  with  severe  pain  and  tenderness  over  the  bones  and 
early  and  peculiar  deformities. 

The  diagnosis  from  osteitis  deformans  and  ostitis  fibrosa  cystica  has 
already  been  considered  under  those  diseases.  Late  rickets  as  seen  in  adults 
does  not  give  the  severe  pain  and  tenderness  so  constantly  present  in 
osteomalacia  nor  the  type  of  deformities.  The  constant  changes  in  the 
epiphyses  and  in  the  skull  in  rickets,  are  never  present  in  osteomalacia. 
Skiagraphs  in  the  two  conditions  are  entirely  unlike. 

Multiple  myeloma  may  resemble  osteomalacia  in  the  stage  previous  to 
the  development  of  marked  deformities.  Pain  and  tenderness  over  the  bones 
are  cardinal  symptoms  in  both  diseases.  Bence-Jones  albumose  if  present 
in  the  urine  is  pathognomonic  of  multiple  myeloma.  The  pelvis  and  the 
spine  are  usually  the  first  bones  involved  in  osteomalacia  while  in  multiple 
myeloma  the  first  symptoms  are  apt  to  appear  in  the  ribs. 


Treatment 

The  closest  attention  to  every  detail  of  the  general  hygiene  is  of  the  first 
importance.  A  full  nutritious  diet  rich  in  calcium  and  phosphorus  (milk, 
eggs,  meat,  fish  and  especially  green  vegetables),  rest,  fresh  air,  hydro- 
therapy and  massage  will  often  bring  about  marked  improvement.  Gestation 
should  be  avoided  and  nursing  forbidden.  Particular  care  is  necessary  that 
the  bed  is  of  suitable  type  to  give  comfort  to  the  patient  and  to  lessen  the 
progress  of  the  deformities  as  well  as  the  dangers  of  fractures.  Mechanical 
supports  of  various  kinds  are  usually  indicated.  Surgical  measures  are 
useless  except  in  the  treatment  of  fractures. 

For  several  decades  the  chief  interest  in  the  treatment  of  osteomalacia 
has  centered  in  measures  concerned  with  the  function  of  the  ovaries  and 
pregnancy.  As  early  as  1876  Porro-^  reported  a  case  of  osteomalacia  with 
apparent  cure  following  the  removal  of  the  uterus  and  ovaries.  Fochier^ 
in  1879  strongly  advocated  this  method.  Fehling'^  in  1891  published  the 
results  in  a  considerable  series  of  cases  treated  by  castration  done  at  the  time 
of  Caesarian  section  and  recommended  the  procedure  in  severe  cases.  Since 
Fehling's  report  ovariotomy  has  been  done  extensively  and  the  result©  have 
been  generally  favorable.  Unquestionably  many  cases  have  been  cured  by 
castration.  The  favorable  results  were  believed  to  be  due  to  a  retention  of 
mineral  substances  in  the  body  following  castration.  McCrudden  has 
proved  experimentally  that  castration  is  without  effect  on  the  general 
metabolism  and  his  exhaustive  work  on  the  subject  seems  to  show  that  the 


ACHONDROPLASIA  475 

improvement  in  osteomalacia  after  oophorectomy  is  due  entirely  to  the 
prevention  of  further  gestation.  The  same  end  has  been  sought  by  the  use  of 
the  X-ray  to  produce  sterility  and  apparently  with  success.  Sterilization 
would  seem  fully  justified  in  the  severe  puerperal  forms  of  the  disease  where 
repeated  pregnancies  have  occurred. 

Bossi^  in  1907  published  excellent  results  from  the  use  of  very  large  doses 
of  adrenalin  given  subcutaneously  (i  c.c.  of  a  i :  1,000  solution  every  second 
day) .  The  experience  of  many  clinicians  with  this  method  has  been  variable. 
It  is  warmly  recommended  by  some  and  condemned  by  others.  This 
treatment  is  without  a  scientific  basis  and  probably  without  merit. 

The  administration  of  phosphorus  while  purely  empirical  has  been  useful 
in  the  hands  of  many  and  seems  to  have  a  place  in  the  treatment  of  the 
disease.  It  is  usually  given  in  o.oi  per  cent,  solution  in  cod  liver  oil,  one 
teaspoonful  three  to  six  times  daily  and  for  a  period  of  months.  If  well 
borne  the  percentage  should  be  gradually  increased  to  0.05  or  0.06.  Some 
prefer  to  use  the  phosphorus  in  pill  form  (Pilulae  Phosphori,  U.S. P.  contain- 
ing phosphorus  0.06  gm.). 


Part  VI 
ACHONDROPLASIA  (CHONDRODYSTROPHIA  FOETALIS) 

Introduction 

Definition. — Achondroplasia  is  a  relatively  rare  disease  of  the  skeleton 
affecting  only  those  bones  formed  from  cartilage  and  invariably  beginning 
in  early  fetal  life.  The  characteristic  features  of  the  disease  at  birth  are  a 
moderately  enlarged  head,  depression  of  the  root  of  the  nose,  trident  hands 
and  remarkably  short  and  curved  extremities  (micromelia),  due  to  arrested 
development  of  the  long  bones,  which  contrast  sharply  with  the  normally 
developed  trunk.  In  the  few  cases  who  survive,  these  characteristics  become 
more  accentuated  and  produce  a  type  of  dwarfism. 

Synonyms. — Rachitis  micromelica  (Winckler,  1871);  achondroplasie 
(Parrot,  1876);  micromelia  chondromalacia  (Kirchberg  and  Marchand, 
1889);  chondritis  foetalis  (Eberth,  Hoess,  Urtel) ;  pseudochondritis 
(Schidlowski) ;  dysplasie  cretinoide  (Klebs) ;  osteosclerosis  congenita 
(Kundrat,  Paltauf) ;  periostale  Aplasie  mit  Osteopsathyrosis  (S.  Miiller) ; 
chondrodystrophia  foetalis  (hyperplastica,  hypoplastica,  malacica)  (Kauf- 
mann);   mikromelia  (Kassowitz). 

In  earlier  writings  the  disease  was  often  classified  under  the  term  osteo- 
genesis imperfecta.     In  France  the  name  achondroplasia  has  come  to  be 


476  ACHONDROPLASIA 

used  almost  universally  while  in  Germany  the  term  chondrodystrophia 
foetalis  is  more  commonly  employed.  The  latter  implying  a  nutritional 
disorder  of  the  cartilage  in  fetal  life  is  more  accurate  than  the  former  which 
signifies  an  entire  absence  of  the  normal  activity  of  the  cartilage  in  pro- 
ducing osseous  tissue,  which  is  not  strictly  the  case  in  this  disease.  Achon- 
droplasia has  the  advantage,  however,  of  priority  and  common  use. 

Historical. — Unmistakable  examples  of  this  disease  are  recorded  in 
medical  writings  for  considerably  more  than  a  century,  but  until  compara- 
tively recent  years  it  was  wrongly  classified  under  a  variety  of  names  but 
chiefly  as  fetal  rickets  or  cretinism.  The  first  case  was  described  by 
Sommering^^  in  1791,  his  report  of  the  autopsy  findings  in  the  case  of  a 
deformed  fetus  making  it  clear  that  he  was  dealing  with  a  typical  example 
of  this  disease. 

Romberg^''  (18 17),  Weber^^  (1829)  and  Busch^  (1836)  each  recorded  a 
case  showing  the  salient  features  of  achondroplasia.  In  each  instance  the 
author  regarded  the  condition  as  fetal  rickets.  In  1856  Virchow^^  reported 
the  first  pathological  studies  of  such  a  case,  also  classifying  the  condition  as 
fetal  rickets.  A  few  years  later  H.  Miiller^'^  (i860)  made  an  exhaustive 
study  of  several  cases  of  the  disease  in  both  man  and  animals  and  showed 
that  the  disease  was  distinct  from  the  ordinary  form  of  rickets  as  seen  in 
children.  He  differentiated  a  congenital  form  of  rickets  as  exemplified  by 
these  cases.  Certain  cretinoid  features  were  recognized  in  the  cases  studied 
and  he  admits  a  possible  relationship  between  the  two.  Miiller  was  the 
first  to  recognize  the  synostosis  of  the  early  bone  centers  at  the  base  of  the 
skull  and  to  attribute  the  bone  changes  to  a  disease  of  the  primordial  car- 
tilage. This  important  work  marks  the  real  beginning  of  our  present 
knowledge  of  the  disease.  The  same  conclusions  were  reached  by  Winckler^^ 
(1871)  and  UrteP^  (1873)  from  histological  studies  of  a  similar  fetus,  the 
former  author  suggesting  the  term  "rachitis  mit  micromelia."  Parrot^" 
(1878)  separated  the  condition  entirely  from  rickets,  congenital  syphilis 
and  cretinism  and  suggested  the  term  achondroplasia.  He  defined  the 
main  process  as  a  dystrophy  of  the  primordial  cartilage  accompanying  the 
first  osteogenetic  growth  in  the  fetus. 

The  most  important  single  contribution  to  the  pathology  of  the  disease 
was  made  by  Kaufmann^^  in  1892-93.  He  advocated  the  name  chondro- 
dystrophia foetalis.  This  author  on  a  pathological  basis  and  as  a  result  of 
most  careful  study  of  fourteen  cases  describes  three  forms  as  follows:  (i) 
Chondrodystrophia  hypoplastica  in  which  the  cartilage  proliferation  is 
diminished  and  the  outward  appearance  of  the  epiphysis  does  not  seem 
changed;  (2)  chondrodystrophia  malacica,  or  chondromalacia  foetalis 
characterized  by  a  softening  and  breaking  down  of  the  epiphyseal  cartilage; 
(3)  chondrodystrophia   hyperplastica   due  to  an  undisciplined  growth  of 


ETIOLOGY 


477 


the  epiphyseal  cartilage  which  is  vascular  and  soft.  The  growth  of  the 
epiphysis  produces  a  marked  enlargement  in  the  region  of  the  joints.  The 
bones  are  harder  than  in  the  other  two  forms  and  more  prone  to  fractures. 

A  remarkably  complete  and  accurate  description  of  the  clinical  features 
of  achondroplasia  was  published  by  Marie^^  in  1900.  Many  important  con- 
tributions have  been  made  to  the  subject  in  recent  years  and  a  summary 
of  all  these  works  is  to  be  found  in  the  exhaustive  discussion  of  the  disease 
by  Rankin  and  Mackay^  and  Emerson''. 

It  is  impossible  to  make  any  exact  statement  regarding  the  incidence 
of  achondroplasia.  Notwithstanding  the  fact  that  it  is  the  most  common 
of  the  congenital  bone  affections  it  must  be  considered  as  relatively  rare. 


Etiology 

Heredity  is  fully  established  as  an  etiologic  factor  of  considerable  impor- 
tance. Marie^^,  Emerson'^  and  several  other  recent  authors  have  presented 
abundant  evidence  from  the  literature  of  direct  inheritance  in  achondro- 
plasia. The  most  striking  and  frequently  quoted  case  of  Porter's^^  presents 
a  record  of  six  typical  examples  of  achondroplasic  dwarfs  in  three  genera- 
tions. All  were  males.  Several  authors  have  also  recorded  more  than  one 
achondroplast  in  a  single  generation.  Emerson  mentions  a  possible  relation- 
ship between  the  disease  and  frequent  and  numerous  pregnancies  as  seems 
to  be  suggested  in  the  records  of  several  cases.  No  recently  compiled 
statistics  regarding  sex  are  available  but  a  slight  preponderance  of  females 
seems  to  exist. 

Many  possible  causes  of  achondroplasia  have  been  suggested,  among 
them  syphilis,  tuberculosis,  infection  and  chronic  intoxications  of  an  heredi- 
tary type,  degeneracy,  nutritive  disturbances  in  the  placenta,  various  me- 
chanical factors  in  utero  affecting  the  embryo  and  disease  of  the  glands  of 
internal  secretion.  Among  earlier  writers  especially  the  disease  was  fre- 
quently regarded  as  a  form  of  rickets  or  cretinism.  Proof  is  entirely  want- 
ing in  all  these  possibilities. 

Jansen^^  in  19 12,  published  an  elaborate  monograph  in  which  he  develops 
a  theory  of  the  nature  and  cause  of  the  disease  which  seems  worthy  of  very 
careful  consideration.  This  author  divides  the  special  features  of  achon- 
droplasia into  two  groups:  (i)  dwarf  phenomena  including  the  short 
extremities  due  to  insufficient  bone  growth,  persistence  of  the  fetal  type  of 
hands,  i.e.,  divergence  of  the  hand  rays  and  resulting  splitting  of  the  fingers 
into  groups  ("main  en  trident"),  deficient  development  of  the  pelvis,  verte- 
bral column,  chest  and,  to  a  slight  degree,  of  the  bones  of  the  basis  cranii. 
These    are    the    most    evident    characteristics    of    achondroplasia;      (2) 


478  ACHONDROPLASIA 

phenomena  of  infolding  or  mechanical  malformations.  These  symptoms 
though  less  conspicuous  than  those  of  dwarf  growth  are  equally  pathog- 
nomonic. They  are  purely  the  result  of  mechanical  forces  which  modify 
the  form  of  the  fetus  and  include  depression  at  the  root  of  nose,  shortening 
of  the  length  and  increase  in  the  transverse  diameter  of  the  base  of  the  skull, 
narrowing  of  the  choana,  dorsolumbar  kyphos. 

Jansen  offers  convincing  evidence  that  the  chief,  if  not  the  only  factor 
in  causing  the  infolding  of  the  embryo  lies  in  the  amnion  which  is  abnormally 
small.  He  explains  that  such  power  on  the  part  of  the  amnion  to  infold  the 
fetus  is  possible  by  the  end  of  the  third  week.  As  direct  amnion  pressure 
causes  infolding  of  the  fetus,  so  indirect  or  hydrostatic  amnion  pressure 
produces  the  phenomena  of  dwarfism.  In  consequence  of  pressure  growth  is 
arrested  as  a  result  largely  of  cell  necrosis.  "Cartilage  in  achondroplasia 
which  suffers  from  famine  at  its  birth  never  outgrows  the  injury."  The 
principle  underlying  the  above  as  stated  by  Jansen  is, "amnion  pressure  is  able 
to  disturb  the  nutrition  and  the  growth  of  part  of  the  embryo,  whilst  the  non- 
affected  parts  continue  their  growth."  Jansen  further  offers  reasonable 
evidence  that  the  so-called  "non-characteristic"  symptoms  of  achondroplasia 
(micrognathy,  agnathy,  harelip,  athyreoplasia,  hydrocephalus,  gas  bubbles 
in  the  lungs,  kidney,  thymus,  liver  and  other  internal  organs,  subcutaneous 
fatty  masses  and  enhanced  sexual  activity)  are  also  due  to  direct  or  indirect 
amnion  pressure. 

Finally  Jansen  formulates  his  thesis  as  follows:  "the  achondroplastic 
is  an  amnion  dwarf,  folded  up  by  a  dwarf  amnion,  by  the  enhanced  hydro- 
static pressure  of  which  it  has  been  disturbed  in  the  development  of  its 
skeleton."  Although  further  proof  of  the  accuracy  of  this  conception  of 
the  cause  of  achondroplasia  is  necessary,  Jansen's  brilliant  arrangement  of 
scientific  data  carries  conviction  and  it  seems  probable  that  his  explanation 
of  the  changes  characteristic  of  the  disease  will  ultimately  be  substantiated. 
Certainly  this  hypothesis  is  the  only  one  among  the  many  advanced  which 
has  a  real  scientific  basis. 

Whatever  the  uncertainties  regarding  the  cause  of  the  disease  may  be, 
the  nature  of  the  process  is  clear.  As  first  pointed  out  by  H.  Miiller  and 
substantiated  by  many  subsequent  investigators  the  seat  of  the  disease  is 
in  the  primordial  bone  cartilage.  The  disease  is  primarily  an  "arrest  or 
perversion  of  the  normal  processes  of  endochondrial  ossification."  The  rows 
of  proliferating  cartilage  cells  are  either  wanting  or  their  normal  arrangement 
is  much  disturbed.  The  result  of  this  distrophy  of  the  bone  cartilage  is  a 
marked  diminution  of  bone  production  and  consequently  an  inhibition  of 
growth  in  the  long  bones.  Those  bones  which  develop  from  membrane  (flat 
bones  and  vault  of  skull)  or  from  cartilage  late  in  fetal  life  are  not 
affected. 


PATHOLOGY  479 


Pathology 

In  consequence  of  the  fact  that  achondroplasia  usually  runs  a  fatal 
course,  i.e.,  the  individual  dying  in  utero  or  soon  after  birth,  abundant 
opportunity  for  pathological  studies  has  existed  and  the  literature  is  espe- 
cially rich  in  pathological  reports  (Virchow^^,  H.  Miiller^^,  Parrot'^,  Ebert^ 
Apert\  Kassowitz^^,  Kaufmann^^,  Porak^^  Porak  and  Durante^^  Schid- 
lowsky27,  Durante^,  Grawitz^",  Kirchberg  and  Marchand^*,  Regnault2^ 
P.  Marie^^  Symington^^,  MacCalluml^  Parhon,  Shunda  and  Zalplachtal^ 
Opie  and  Allison^^,  Symmers  and  Wallace^").  No  autopsy  on  an  adult 
achondroplast  has  ever  been  recorded.  The  essential  lesions  of  the  disease 
are  in  the  bony  structures  although  certain  and  variable  changes  may  be 
present  in  the  soft  parts. 

General  Deformities 

The  general  appearances  of  the  fetus  with  this  affection  are  striking 
and  entirely  distinct  from  those  seen  in  any  other  disease.  A  diagnosis  can 
readily  be  made  on  inspection.  The  infant  is  usually  plump  and  the  thick- 
ened skin  is  thrown  into  folds  especially  about  the  joints,  an  appearance 
which  Weber^^  describes  as  "a  dwarf  with  much  too  large  clothes."  A  dis- 
proportionately large  head  and  normally  developed  trunk  contrast  sharply 
with  the  very  short  but  usually  well  formed  extremities.  As  a  result  of  the 
micromelia  or  phacomelia  the  stature  is  much  abbreviated.  The  depression 
of  the  root  of  the  nose  gives  it  a  peculiar  saddle  form  or  pug  nose  appearance. 
The  prominent  lower  jaw  (prognathus),  thick  lips  and  protruding  tongue 
suggest  cretinism.  A  marked  prominence  of  the  abdomen  is  the  rule. 
Throughout  the  body  the  changes  are  almost  strictly  symmetrical. 

Individual  Deformities 

In  the  normal  infant  the  central  point  of  the  body  Is  at  the  navel  but 
in  the  achondroplast  the  disproportion  between  the  legs  and  trunk  raises  the 
point  to  the  zyphoid  cartilage.  Instead  of  the  average  normal  length  of  the 
fetus  of  50  cm.  (Kaufmann)  these  cases  measure  from  30  to  40  cm.  and  a 
few  are  recorded  considerably  under  30  cm. 

The  head  shows  a  varying  degree  of  enlargement  and  may  be  hydro- 
cephalic (Fig.  15).  Kassowitz^^  studied  the  relation  of  the  circumference  of 
the  head  to  the  body  length  and  gives  the  figures  for  the  normal  new-born  as 
33  cm.  for  the  former  and  50  cm.  for  the  latter;  or  a  percentage  of  66.6.  He 
quotes  figures  for  achondroplasia  varying  from  seventy-five  to  one  hundred 


48o  ACHONDROPLASIA 

and  twenty  per  cent. ;  in  other  words,  in  this  disease  the  circumference  of  the 
head  often  equals  or  considerably  exceeds  the  total  body  length.  It  should  be 
noted,  however,  that  the  macrocephaly  is  often  more  apparent  than  real.  The 
skull  is  not  strikingly  changed  in  shape  except  for  a  considerable  prominence 
of  the  frontal  region  and  a  tendency  to  the  brachycephalic  type.  In  con- 
trast to  the  condition  found  in  osteopsathyrosis  the  cranial  bones  are  well 
formed  and  hard  and  the  fontanelle  and  sutures  normal  or  permaturely 
closed. 

The  bones  of  the  skull  base  are  largely  formed  from  cartilage ;  hence  like 
the  long  bones  they  play  a  prominent  part  in  the  achondroplastic  process. 
The  changes  are  exceedingly  variable,  some  parts  being  normal  while  others 
are  abnormal.  Premature  union  of  the  bones  and  arrest  of  development  are 
the  two  most  important  conditions  found. 

The  OS  tribasilaris  (Virchow)  at  the  time  of  birth  is  composed  of  three 
separate  parts,  the  basilar  portion  of  the  occipital  bone  and  the  two  portions 
of  the  sphenoid  which  are  united  by  synchondrosis.  The  synchondrosis 
between  the  two  sphenoids  normally  ossifies  soon  after  birth  but  the  syn- 
chondrosis between  the  occipital  and  the  sphenoid  bones  does  not  become 
bony  until  adult  life.  These  bones  are  often  firmly  united  at  birth  in  the 
achondroplastic  fetus  and  according  to  most  authorities  it  is  this  premature 
synostosis  which  is  largely  responsible  for  the  retardation  in  the  growth  of 
the  basis  cranii  and  the  resulting  deformities.  Likewise  the  bony  union  of 
the  four  bones  surrounding  the  foramen  magnum  should  not  occur  until 
about  the  sixth  year  but  they  are  usually  completely  synostosed  at  birth 
in  this  disease.  Jansen^^  is  convinced  that  the  usual  conception  that  this 
synostosis  is  the  cause  of  the  shortening  of  the  basis  cranii  is  entirely  erron- 
eous and  supports  his  opinion  by  convincing  arguments.  He  contends  that 
the  reverse  is  true,  i.e.,  the  early  fusion  is  the  result  of  shortening  of  the  base 
and  not  the  cause.  The  changes  in  the  skull,  in  other  words,  are  according 
to  Jansen  largely  mechanical  malformations  due  to  infolding  which  are  of 
much  greater  moment  than  the  trophic  disturbances.  A  participation  of 
the  nasal  and  ethmoid  bones  in  this  process  accounts  for  the  deformity  of 
the  nose.  Prognathus  is  also  associated  with  these  changes.  Dentition 
is  seldom  abnormal.  In  the  most  severe  cases  the  sella  turcica  is  often 
greatly  reduced  in  size  (Jansen). 

The  vertebral  column  rarely  escapes  but  the  alterations  are  not  very 
noticeable.  Jansen  says  that  the  vertebrae  diminish  in  size  from  above 
downward  which  is  the  exact  reverse  of  the  normal  spine.  A  dorsolumbar 
kyphosis  can  always  be  demonstrated  (Fig.  i6).  Wheeldon^^  has  recently 
described  a  "wedged  shaped  vertebra"  in  several  achondroplastic  children 
which  he  interprets  as  a  result  of  amnion  pressure. 

Porak^^  particularly  emphasizes  the  fact  that  the  trunk  shows  a  normal 


Fig.  15. — Achondroplasia.  Skeletr'i  of  seven 
months  foetus.  (Warren  Museum,  Harvard  Medi- 
cal School.) 


A.     Facing  480 


Fig.  1 6. — Achondroplastic  Dwarf. 


Age  23,  height  3  feet    10  inches. 


B.     Facing 


PATHOLOGY  481 

development.  This  is  true  in  many  cases  and  the  changes  in  the  thorax 
are  never  striking  but  nevertheless  alterations  indicating  arrested  develop- 
ment in  the  ribs  do  occur.  The  thorax  is  sometimes  small  above  and  broad- 
ened below.  A  projecting  sternum  and  flattening  of  the  chest  have  been 
observed.  Several  authors  have  described  a  well  marked  rosary  similar 
to  the  rachitic  rosary  but  the  enlargement  at  the  junction  of  the  cartilage 
and  ribs  is  not,  as  is  the  case  in  rickets,  due  to  cartilage  proliferation  but 
to  bony  overgrowth  from  the  epiphyseal  cartilage  of  the  rib  (Frangenheim®). 
This  thickening  is  more  marked  on  the  inner  thorax  wall  than  the  outer. 
The  clavicle  and  scapula  usually  escape  noteworthy  changes  except  that 
they  are  apt  to  be  somewhat  below  the  normal  in  size.  The  same  general 
type  of  changes  resulting  from  arrested  bone  development  is  seen  in  the 
pelvis.  It  is  misshapen  and  flattened  as  a  result  of  early  synostosis  and 
arrested  osseous  growth.    The  sacrum  and  coccyx  develop  normally. 

The  most  remarkable  and  interesting  changes  are  found  in  the  bones  of  the 
extremities,  especially  the  femur  and  humerus  (Figs.  17  and  18).  In  general 
these  long  bones  show  first  of  all  a  shortening  of  from  one-third  to  one-half 
in  length  in  which  the  epiphysis  does  not  participate  (Frangenheim).  The 
fibula,  however,  as  first  mentioned  by  Marie  is  relatively  longer  than  the  tibia. 
The  diameter  of  the  diaphysis  is  not  far  from  the  normal  thus  giving  to  the 
bones  a  very  short  but  massive  appearance.  The  shaft  may  be  straight 
but  is  more  often  curved  to  a  pronounced  degree.  As  the  bones  are  hard 
and  compact  fractures  are  but  very  rarely  seen.  The  malformation  in  the 
epiphysis  is  quite  as  striking  as  that  of  the  diaphysis.  This  portion  of  the 
bone  shows  an  enormous  hypertrophy  which  takes  the  form  of  an  irregular 
mushroom  growth.  In  consequence  of  this  cartilaginous  overgrowth  motion 
in  the  joints  of  the  extremities  is  often  limited  and  sometimes  entirely  lost. 
More  or  less  flexion  is  the  rule.  The  joint  surfaces  are  normal  and  arthritis 
does  not  occur.  Notwithstanding  the  fact  that  the  bones  of  the  hands  and 
feet  develop  from  cartilage  the  involvement  in  them  is  not  very  conspicuous. 

On  section  the  affected  bones  present  very  abnormal  and  varied  appear- 
ances. There  is  evidence  that  periosteal  bone  production  is  active  where 
endochondrial  ossification  is  wanting.  The  cortex  of  the  shaft  is  thickened 
and  the  periosteum  active.  Many  osteoblasts  are  present.  For  the  most 
part  a  fairly  regular  system  of  trabeculae  is  found.  The  medullary  canal 
is  often  wanting  but  the  marrow  spaces  are  numerous  and  enlarged.  The 
marrow  is  vascular  and  rich  in  round  and  spindle  cells  as  well  as  red 
blood  corpuscles.  Giant  cells  are  sometimes  abundant  suggesting  bone 
absorption.  Bone  absorption  does  occur  and  may  progress  to  such  an 
extent  that  fractures  take  place  but  such  an  occurrence  is  rare.  Osteo- 
sclerosis occasionally  complicates  the  picture. 

The  huge  cartilaginous  ends  of  the  bones  show  even  greater  changes 
Vol.  IV.  31 


482  ACHONDROPLASIA 

than  are  found  in  the  shaft.  In  some  cases  the  tissue  has  the  structure  of 
normal  hyahne  cartilage  in  a  state  of  active  growth.  More  commonly  the 
cartilage  structure  is  grossly  abnormal.  MacCallum^^  describes  "a  peculiar 
disappearance  of  the  normal  homogeneous  matrix,  so  that  the  cartilage  cells 
are  single  or  in  little  groups  \vhich  hang  together  in  a  network."  Connec- 
tive tissue  metaplasia  is  common.  Vacuolation  has  frequently  been  men- 
tioned. The  most  important  and  characteristic  change  in  the  cartilage  in 
chondrodystrophia  foetalis  is  the  marked  aplasia  in  the  zone  of  ossification. 
Kaufmann^^  says  "in  all  cases  there  is  a  more  or  less  complete  inhibition  of 
the  normal  row  formation  of  the  proliferating  cartilage  cells  in  the  prepara- 
tory stage  of  ossification."  It  is  this  aplasia  in  the  zone  of  proliferating 
cartilage  at  the  epiphyseal  line  which  explains  the  diminution  in  the  power 
of  length  growth  in  the  long  bones.  A  peculiar  and  constant  lesion  in  all 
severe  cases  is  the  continuation  of  the  periosteum  inward  for  a  variable  dis- 
tance betsveen  the  diaphysis  and  epiphysis.  It  was  first  noted  by  UrteP^ 
who  regarded  it  as  a  factor  in  limiting  the  endochondrial  bone  formation. 

In  a  considerable  number  of  cases  lesions  of  other  tissues  and  of  the 
internal  organs  have  been  reported  but  they  are  too  varied  and  inconstant 
to  suggest  that  any  are  characteristic  of  achondroplasia. 


.  Varieties 

Mention  was  made  above  of  the  anatomic  classification  suggested  by 
Kaufmann  of  achondroplasia  into  three  general  groups,  viz.:  (i)  chondro- 
dystrophia hypoplastica,  (2)  chondrodystrophia  malacica  and  (3)  chon- 
drodystrophia hyperplastica.  Variot^^  also  divides  the  disease  into  the 
hypoplastic  (achondroplasie  vraie  of  Parrot)  and  the  hyperplastic  forms  in 
accordance  with  differences  seen  in  X-rays  of  living  cases.  Regnault-^ 
speaks  of  limited  forms  of  the  disease  in  which  the  skull  alone  or  the  skull 
and  the  upper  extremities  are  the  only  parts  involved.  Dufour'*  describes 
an  atypical  form.  Jansen^^  contends  that  achondroplasia  appears  in  varying 
degrees  and  that  the  forms  described  by  Regnault  and  Dufour  are  really 
mild  forms  of  the  disease.  Patients  may  show  symptoms  typical  of  chon- 
drodystrophia but  limited  to  only  a  portion  of  the  body.  It  seems  probable 
that  the  various  types  described  are  only  different  grades  of  the  same 
disease.  As  a  rule  it  is  only  the  mild  cases  which  survive  and  these  seem  to 
conform  in  a  general  way  to  the  hypoplastic  form  of  Kaufmann.  Opie  and 
Allison^^  have  recently  published  a  careful  stud}'  of  two  cases  and  conclude 
that  their  "observ^ations  establish  the  occurrences  of  hypertrophic  chondro- 
dystrophy as  a  disease  of  postfetal  life,  and  show  that  associated  abnormal 
endochondral  osteogenesis  may  persist  throughout  adolescence." 

Certain  changes  in  the  soft  tissues  seen  in  achondroplasts  strongly  sug- 


Pjg_    i7._  Achondroplasia.      X-ray  of  lower  leg  of  patient  shown  in 
Figure  1 6. 
A.     Facing  482 


mmt 


Fig.  1 8. — Achondroplasia.    X-ray  of  arm  of  patient  shown  in  Figure  i6. 
B.    Facing  482 


SYMPTOMS  483 

gest  a  close  relationship  between  the  disease  and  cretinism.  Symmers  and 
Wallace^*',  in  1913,  studied  five  cases  of  fetal  chondrodystrophy  and  claim 
to  have  established  the  fact  that  at  least  in  a  certain  proportion  of  cases 
there  is  an  intimate  association  with  cretinism.  Significant  pathological 
lesions  in  the  thyroid  gland  were  demonstrated  in  all  of  their  cases.  There 
is  no  evidence,  however,  that  the  cretinism  bears  any  causal  relationship 
to  the  changes  in  the  skeleton. 

Symptoms 

The  symptoms  are  essentially  objective  and  have  already  been  mentioned 
under  pathology.  The  moderately  large  head  of  the  brachycephalic  type, 
rather  small  and  cretinoid  features,  depression  of  the  root  of  the  nose, 
prognathus,  normally  developed  trunk  contrasting  with  the  short  and  plump 
extremities,  lordosis,  trident  hands,  protuberant  abdomen,  general  increase 
in  the  subcutaneous  fat  and  loose  integument  are  constant  features  of  the 
achondroplastic  fetus.  With  very  rare  exceptions  these  infants  are  still- 
born or  die  in  the  early  months  of  life.  The  few  who  survive  the  first  year 
or  two  develop  without  impairment  of  their  general  health  and  apparently 
have  the  same  expectation  of  life  as  do  normal  individuals.  The  great  ma- 
jority of  adult  dwarfs  are  of  this  so-called  achondroplastic  type. 

In  early  years  the  adiposity  disappears  and  the  skin  gradually  takes  on 
a  normal  appearance.  The  fetal  deformities  of  the  skeleton  persist  but 
otherwise  the  development  of  the  child  is  essentially  normal.  Except  for 
occasional  instances  of  hyperplasia  of  the  teeth,  dentition  is  not  defective. 
Organic  functions  are  normal.  Kassowitz^^  mentions  a  relaxed  condition 
of  some  of  the  joints  and  especially  the  knees  but  such  an  occurrence  is  the 
exception.  Opinions  differ  widely  as  to  the  mentality  and  disposition  of 
these  cases.  Ballester^  says  "such  patients  are  docile,  kind,  subnormal  in 
intelligence,  credulous  as  children  and  obedient."  By  others  they  are  said 
to  be  ill-tempered,  quarrelsome,  lascivious  and  to  possess  an  infantile  intel- 
lect. It  is  evident  from  a  study  of  the  reported  cases  that  the  mentality 
and  disposition  vary  considerably  but  in  the  vast  majority  seem  to  be 
normal.  Sexual  growth  as  a  rule  progresses  as  in  other  children  although 
a  few  instances  are  on  record  of  an  extraordinarily  early  development. 

The  adult  achondroplast  is  a  deformed  dwarf  and  with  slight  modifica- 
tions due  to  growth  presents  the  same  general  characteristicsas  are  seen  in  the 
fetal  stage  (Fig.  15).  The  same  decentralization  of  the  body  is  present,  the 
central  point  being  at  the  zyphoid  cartilage  or  slightly  higher  instead  of  at 
the  symphysis  pubis  as  is  the  case  in  normal  adults.  A  very  striking  feature 
is  the  abnormal  development  of  the  skeletal  muscles,  which  gives  the 
achondroplastic  dwarf  a  strength  relatively  much  greater  than  the  normal 


484  ACHONDROPLASIA 

man.  The  posture  is  erect  and  the  spine  perfectly  straight  except  in  the 
lumbar  region  where  there  is  marked  lordosis  due  to  the  forward  tilting  of 
the  sacrum.  Emerson'^  gives  the  average  height  of  eighteen  achondroplastic 
males  as  119  cm.  and  of  eighteen  women  as  116  cm.  The  ratio  of  the  cir- 
cumference of  the  head  to  the  total  body  length  is  much  greater  than  in 
individuals  of  normal  stature.  A  decided  brachycephalic  or  globular  type 
of  head  (increased  cephalic  index)  and  prominence  of  the  frontal  and 
parietal  portions  are  constantly  present.  The  face  is  actually  large  but 
appears  small  in  consequence  of  the  enlarged  calvarium.  All  of  the  features 
are  somewhat  coarse  but  the  nose  in  particular  shows  constant  changes. 
The  whole  nasal  region  is  flattened  with  an  especially  well  developed  retrac- 
tion at  its  root.  The  end  is  hypertrophied  and  rounded.  The  extremities 
are  symmetrically  and  about  equally  involved,  but  in  both  the  arms  and 
legs  the  greatest  shortening  is  in  the  proximal  or  root  segment  (rhizomelia). 
Relative  shortening  of  the  tubular  bones  increases  with  growth  and  the 
disproportionate  size  of  the  epiphyses  becomes  more  marked.  The  arms 
are  so  much  shortened  that  the  finger  tips  which  normally  reach  to  the  mid 
thigh  barely  touch  the  crest  of  the  ilium.  Complete  extension  of  the  elbow 
joint  is  impossible  and  motion  in  the  shoulder  articulation  is  usually  some- 
what limited.  The  bones  are  only  slightly  curved.  The  hands  are  diminu- 
tive, short,  broad  and  pudgy.  All  of  the  fingers  are  of  about  equal  length 
and  tapering,  and  distal  to  the  second  joint  are  separated  from  each  other 
like  the  spokes  of  a  wheel  or  trident;  hence  the  name  "main  en  trident" 
(Marie).  Equally  marked  dwarf  characteristics  are  present  in  the  legs  and 
the  femur  and  tibia  are  apt  to  show  considerable 't)owing.  Malposition  of 
the  knee  joint  and  relaxation  of  the  joints  of  the  toes  are  common. 

The  sexual  organs  are  normally  or  overdeveloped  while  an  exaggeration 
of  sexual  functions  is  not  unusual.  This  enhanced  sexual  appetite  is  com- 
mon to  both  sexes.  A  considerable  list  of  abnormalities  may  be  cited  as 
occasionally  seen  in  achondroplasia.  Jansen  considers  harelip,  micrognathy 
and  agnathy,  myxedema  and  hydrocephalus  as  non-characteristic  symp- 
toms of  the  disease. 

X-rays  show  particularly  characteristic  appearances  in  achondroplasia 
which  are  unlike  those  seen  in  rickets  and  retinism,  the  two  conditions 
with  which  the  disease  is  sometimes  confused.  They  confirm  the  pathologi- 
cal findings  as  regards  the  size  and  shape,  of  the  affected  bones.  Fussel  and 
Pahcoast^  have  described  the  abnormalities  in  growth  of  the  epiphysis  and 
shaft  as  well  as  in  osseous  structure.  They  consider  the  appearances  in  the 
hands  and  feet  especially  as  peculiar  and  unique.  The  abrupt  expansion  of 
the  shaft  at  its  epiphyseal  end  and  the  deficient  and  irregular  ossification 
at  this  point  are  important  features.  A  localized  and  very  abrupt  bowing 
at  the  upper  end  of  the  tibia  and  lower  end  of  the  femur  also  contrasts  with 


TREATMENT  485 

the  broad  curve  of  rickets.  The  shaft  of  the  long  bones  is  dense  and  fairly 
uniform.  All  ridges  for  the  attachment  of  muscles  are  enlarged  and  the 
normal  angles  accentuated. 


Course  and  Prognosis 

Nearly  all  cases  die  between  the  seventh  and  ninth  month  of  intra- 
uterine life.  Of  those  living  at  birth  the  majority  succumb  within  the  first 
few  months.  The  few  who  survive  the  first  year,  probably  representing  the 
mild  type  of  the  disease,  seem  to  have  a  normal  chance  of  life.  In  spite  of 
the  dwarfism  these  individuals  often  possess  a  physical  vigor  considerably 
above  the  normal.  Numerous  cases  are  found  in  the  literature  who  have 
lived  to  extreme  old  age.  Since  achondroplasia  is  primarily  the  result  of 
deficient  bone  growth  the  disease  does  not  advance  after  the  time  when  bone 
growth  normally  ceases. 

Diagnosis 

The  principal  diagnostic  features  of  achondroplasia  are  the  fetal  origin, 
macrocephalic  and  brachycephalic  head, ,  depressed  root  of  nose  and  prog- 
nathus,  normal  trunk,  stunted  growth  of  the  extremities  with  resulting 
decentralization  of  the  mid  point  of  the  body,  bone  deformities,  lordosis, 
"main  en  trident,"  general  excess  of  subcutaneous  fat  with  thickened,  loose 
skin,  protuberant  abdomen,  normal  mentality  and  the  X-ray  findings.  If 
these  characteristics  are  kept  in  mind  achondroplasia  should  never  be  con- 
fused with  any  other  condition. 

The  differentiation  from  osteopsathyrosis  is  discussed  under  that  disease. 
Mongolism  bears  no  real  resemblance  to  achondroplasia.  The  subject  of 
the  former  is  an  idiot,  shows  facial  characteristics  entirely  unlike  those  of 
achondroplasia  and  suffers  from  none  of  the  skeleton  changes  of  the  latter. 
Cretinism  is  sometimes  confused  with  this  disease  since  the  chondro- 
dystrophic  infant  often  presents  certain  changes  in  the  face  which  are  sug- 
gestive of  cretinism.  The  cretin  is  feeble  minded  and  shows  the  objective 
signs  of  myxedema.  Rickets  is  probably  a  rare  complication  of  achon- 
droplasia in  children  but  bears  no  close  resemblance  to  it.  The  X-ray  find- 
ings will  differentiate  the  process  in  the  bones  in  the  two  conditions. 


Treatment 

Beyond  the  employment  of  measures  to  improve  the  general  nutrition 
treatment  is  of  no  avail. 


Part  VII 

HEREDITARY  DEFORMING  CHONDRODYSPLASIA 

(MULTIPLE  CARTILAGINOUS  EXOSTOSES) 

Introduction 

Definition. — This  is  an  hereditary  disease  of  congenital  origin  show- 
ing as  its  most  characteristic  features  multiple  cartilaginous  and  osteo- 
cartilaginous growths,  chiefly  on  the  metaphyseal  portion  of  the  bones, 
and  secondary  skeletal  deformities  resulting  from  early  developmental 
defects. 

Synonyms. — Multiple  cartilaginous  exostoses  (Virchow) ;  hereditary 
multiple  exostoses;  multiple  cancellous  exostoses;  ossified  diathesis;  rha- 
chitiform  enchondrosis ;  exostoses  epiphysaires  nombreuses;  exostoses 
osteogeniques  multiples,  or  hereditaires  or  familiales  (Curtillet) ;  exostoses 
juxtaepiphysaires;  exostoses  congenitales  symmetrique  nombreuses;  dys- 
chondroplasia;  Wachstums-exostosen ;  chondral  or  exostatic  dysplasia 
(Kienbock) ;  multiple  congenital  osteochondromata  (Boggs) ;  hereditary 
deforming  chondrodysplasia  (Ehrenfried) ;  diaphysial  aclasis  (Roberts); 
multiple  cancellous  osteomata  (Lett);  multiple  chondroosteomata  (Percy); 
dystrophia  ossea  congenita  (de  Josselin  and  de  Jong).  The  term,  hereditary 
deforming  chondrodysplasia,  suggested  by  Ehrenfried^,  best  describes  the 
disease,  but  the  most  commonly  employed  designation  is  multiple  cartil- 
aginous exostoses. 

Among  the  very  early  anatomical  writings  the  exostoses  were  repeatedly 
described  as  interesting  bone  anomalies  but  the  recognition  of  the  con- 
dition as  a  definite  disease  did  not  occur  until  much  later.  During  the 
past  hundred  years  a  large  number  of  cases  have  been  reported  and  the 
condition  much  studied,  though  until  very  recent  years  almost  exclusively 
by  the  French  and  German  authors.  The  first  case  recorded  in  this  country 
was  reported  by  Gibney^  in  1875.  A  very  exhaustive  and  critical  review 
of  the  voluminous  literature  was  published  by  Frangenheim'^  in  191 2. 
In  191 5  Ehrenfried'*  was  able  to  collect  approximately  six  hundred  cases 
reported  in  three  hundred  articles.  The  same  author^  in  191 7  assembled 
ninety-nine  from  the  American  literature.  The  large  number  reported  in 
very  recent  years  and  especially  the  relatively  large  series  personally  studied 
by  various  authors  indicates  that  the  affection  is  not  rare.  This  illus- 
trates what  so  often  happens,  namely,  that  rarer  diseases  are  often  over- 
looked because  not  considered  among  the  possibilities. 

486 


ETIOLOGY  487 


Etiology 

Little  is  known  regarding  the  etiology  of  the  disease.  Numerous 
theories  to  account  for  the  peculiar  bone  changes  have  been  suggested. 
The  disease  has  been  attributed  to  bacterial  infections,  syphilis,  rickets, 
disturbances  of  the  central  nervous  system  and  trophic  nerves,  and  to 
abnormal  function  of  the  endocrine  glands,  especially  the  thyroid,  but  none 
have  the  support  of  clinical  or  experimental  evidence  and  it  seems  evident 
that  the  disease  does  not  find  its  origin  in  any  of  these  factors.  The  most 
probable  hypothesis  is  that  multiple  cartilaginous  exostoses  represent  a 
"disturbance  in  development  of  the  intermediary  cartilage  due  to  an  original 
defective  anlage"  (v.  Bergmann^).  In  elaboration  of  this  view  Keith^*' 
quotes  Hunter's  teaching  regarding  the  nature  of  bone  growth.  He  de- 
scribed a  double  process,  first,  the  laying  down  of  new  osseous  tissue  in 
the  diaphysial  lines  and  second,  the  new  bone  rebuilt  structurally  and 
made  a  part  of  the  shaft.  According  to  Keith  this  "modeling  process"  is 
arrested  in  hereditary  deforming  chondrodysplasia.  This  defective  evolu- 
tion in  bone  growth  is  usually  termed  chondrodysplasia. 

Age. — The  process  in  the  bones  is  definitely  associated  with  the  period 
of  bone  development  and  probably  in  all  cases  begins  in  early  infancy. 
In  the  early  stages  the  presence  of  the  exostoses  may  be  unrecognized 
unless  shown  by  the  X-rays  but  with  bone  growth  in  subsequent  years 
the  tumors  gradually  increase  in  size.  The  chief  manifestations  of  the 
affection  seldom  appear  prior  to  the  fourth  to  sixth  year  and  often  not 
until  later.  The  age  period  at  which  the  exostoses  are  usually  first  noted 
has  been  studied  by  Honeij^  in  sixty -six  cases;  fourteen  were  between  one 
and  ten  years,  seven  between  ten  and  fifteen  years,  eleven  between  fifteen 
and  twenty  years,  nine  between  twenty  and  twenty-five,  ten  between 
twenty-five  and  thirty,  and  fourteen  over  thirty  years.  X-ray  examina- 
tions in  a  considerable  number  of  cases  make  it  seem  evident  that  by  this 
means  the  early  lesions  can  be  demonstrated  soon  after  birth. 

Sex. — The  disease  predominates  in  the  male  sex.  In  eighty-nine  cases 
Ehrenfried^  found  a  ratio  between  the  males  and  females  of  3:1.  Percy's^^ 
ratio  of  males  to  females  among  the  thirty  members  of  a  single  family 
investigated  for  four  generations  was  5:1. 

Heredity. — The  condition  is  clearly  hereditary.  Among  two  hundred 
and  thirty-six  cases  studied  by  Ehrenfried^  direct  heredity  was  found  in 
one  hundred  and  seventy-six  and  this  author  concludes  "that  familial 
occurrence  is  demonstrable  in  the  majority  of  cases."  In  seventy-six  cases 
collected  by  him,  where  special  inquiry  was  made  regarding  inheritance,  posi- 
tive evidence  was  found  in  sixty-three  occurring  in  ten  families,  or  eighty- 


488  HEREDITARY  CHONDRODYSPLASIA 

three  per  cent.  Reinecke^^  investigated  thirty  families  having  members 
with  exostoses  and  found  the  disease  present  in  two,  three,  four  and  five 
generations.  Percy^^  traced  one  exostotic  family  through  four  generations. 
Among  the  one  hundred  and  thirteen  individuals  twenty-five  males  and 
five  females,  or  26.5  per  cent.,  were  found  affected.  Ehrenfried^  reports 
eight  cases  in  three  generations  comprising  eighteen  individuals. 

Transmission  of  the  disease  is  more  frequent  through  the  males,  in 
which  sex  it  predominates,  but  there  is  no  case  on  record  where  trans- 
mission has  taken  place  through  an  unaffected  male  as  may  occur  through 
an  unaffected  female  (Ehrenfried^  Reinecke^^  Ashhurst^).  The  inheritance 
is  usually  immediate  from  parent  to  offspring.  The  parent  may  have 
enchondromata  and  the  child  true  exostoses,  or  the  reverse  may  occur. 


Pathology 

The  pathological  changes  in  the  bones  in  this  disease  present  a  very 
complex  and  somewhat  confused  picture  depending  on  the  extent  and 
severity  of  the  process.  The  gross  lesions  may  be  grouped,  (i)  as  those 
associated  with  the  formation  of  chondroma  or  osteochondroma,  and  (2) 
those  resulting  from  arrested  bone  development.  Perrin^^  speaks  of  the 
exostoses  and  disturbances  of  growth  in  hereditary  deforming  chondro- 
dysplasia as  "different  manifestations  which  are  habitually  associated  and 
with  parallel  evolution."  There  appears  to  be  abundant  proof  that  the 
cause  of  the  bony  outgrowths  as  well  as  the  deformities  due  to  growth 
retardation  lies  in  a  disorder  of  the  intermediary  cartilage,  i.e.,  a  chondro- 
dysplasia, affecting  chiefly  the  metaphysis  of  the  long  bones  and  to  a  less 
extent  the  scapula,  clavicles,  spine,  ribs  and  pelvis.  The  origin  of  osseous 
abnormalities,  in  other  words,  lies  in  a  "disturbance  in  the  proliferation 
and  ossification  of  the  intermediary  cartilage  during  the  period  of  growth" 
(Ehrenfried^) .  This  fact  explains  the  absence  of  changes  in  the  bones 
of  the  face  and  cranium  which  develop  from  membrane. 

The  microscopic  appearances  of  the  cartilage  are  those  of  a  greatly 
disordered  and  excessive  growth.  Throughout  the  area  between  the 
epiphysis  and  diaphysis  (zone  of  proliferation)  are  irregular  masses  of 
cartilage  cells  without  orderly  arrangement  and  with  only  incomplete 
ossification  in  occasional  groups.  The'  intermediary  cartilage  itself  is 
often  thin  and  very  irregular  in  outline  as  in  the  case  of  the  cartilage  at 
the  distal  end  of  the  radius.  In  some  cases  very  early  ossification  of  the 
cartilage  occurs  leading  to  premature  union  of  the  epiphysis  and  diaphysis. 
According  to  most  authors  the  epiphysis  is  but  little  if  any  changed  except 
in  the  more  severe  cases  where  it  is  often  considerably  distorted  and  di- 


PATHOLOGY  489 

minished  in  size.  Honeij^  in  a  roentgenological  study  of  four  cases  found 
rather  striking  enlargement  in  the  epiphyses  and  concludes  that  moderate 
metaplastic  changes  frequently  occur  and  even  unrestricted  growth  may 
rarely  take  place.  The  periosteum  of  the  affected  bones  is  to  a  moderate 
degree  thickened  and  shows  evidence  of  abnormal  activity.  Here  and 
there  beneath  the  periosteum  near  the  end  of  the  bone  are  seen  nests  of 
uncalcified  cartilage  cells. 

The  most  characteristic  changes  in  chondrodysplasia  concern  the 
metaphyseal  portions  of  the  long  bones  and  especially  of  the  femur,  tibia, 
fibula,  ulna  and  radius.  The  essential  lesion  in  these  locations  is  a  strik- 
ing overgrowth  of  bone  which  appears  as  an  extremely  irregular,  ragged, 
often  cauliflower-like  proliferation  of  the  bone  (Fig.  19).  It  may  encroach 
slightly  on  the  epiphysis  and  even  interfere  with  free  movement  in  the 
joint.  Except  for  the  ends  of  the  shaft  the  structural  alterations  in  the 
diaphysis  are  not  significant. 

Exostoses  are  the  most  striking  feature  of  the  disease  (Fig.  19).  They  may 
befewin  number  or  exceedingly  numerous.  In  Woodward's  case  (seeTurner^^) 
one  hundred  and  eighty  tumors  of  the  skeleton  were  counted  during  life. 
They  vary  in  size  from  a  small  spur  to  a  tumor  of  many  centimeters  in 
diameter.  Their  distribution  is  in  general  symmetrical  but  instances  of 
a  more  or  less  strict  unilateral  arrangement  on  the  skeleton  have  been 
recorded.  The  location  of  the  tumors  is  almost  exclusively  on  the  dia- 
physial ends  of  the  bones,  though  small  ones  do  develop  along  the  central 
portion  of  the  shaft.  The  parts  forming  the  knee,  ankle,  hip  and  wrist  are 
the  most  frequent  sites.  In  outer  form  the  exostoses  are  extremely  varied 
but  commonly  are  irregularly  rounded  or  lobulated.  The  exostoses  are 
covered  with  dense  cartilage  and  may  show  bursae  on  their  outer  surface. 
Small  portions  of  the  tumor  sometimes  become  separated  and  remain  in 
the  bursa  as  floating  bodies.  True  enchondromas  are  often  associated 
with  the  exostoses.  Both  the  enchondromata  and  the  exostoses  take 
their  origin  in  the  cartilage  formed  at  the  epiphyseal  line,  small  islands 
of  which  through  a  process  of  infolding  may  become  separated  with  and 
the  bone  growth  carried  along  under  the  periosteum.  If  excessive  growth 
in  the  lower  end  of  the  tibia  or  ulna  occurs  a  pseudarthrosis  or  synostosis 
with  the  companion  bone  often  results. 

On  section  the  tumors  are  seen  to  be  covered  with  a  thick  glistening 
cartilage  throughout.  Beneath  the  enveloping  cartilage  is  a  layer  of 
hyaline  cartilage  and  osseous  tissue  of  variable  thickness.  In  this  layer 
some  trabecular  structure  is  present.  The  central  portion  of  the  growth 
contains  more  lime  salts  and  the  denser  bone  is  continuous  with  the  under- 
lying cortex.  The  presence  of  marrow  spaces  and  an  actual  lamellar  ar- 
rangement like  normal  bone  is  described  by  some.    The  interior  of  the  tumor 


490  HEREDITARY  CHONDRODYSPLASIA 

is  sometimes  rich  in  connective  tissue  and  blood  vessels.  As  the  result  of 
fracture  the  exostosis  is  occasionally  separated  from  the  bone  and  becomes 
a  floating  body. 

Skeletal  growth  retardation  forms  a  less  conspicuous  part  of  the  disease 
but  is  regarded  by  many  authors  as  the  essential  feature  (Lenormant^^ 
Bessel-Hagen-,  Perrin^^,  Ehrenfried^,  Ashhurst\  Honeij^  and  others). 
The  results  of  arrested  growth  in  mild  cases  are  so  slight  as  to  be  difficult 
of  demonstration  but  in  all  severe  cases  are  clearly  marked.  Their  dis- 
tribution is  the  same  as  the  exostoses  since  both  have  a  common  origin 
in  the  chondrodysplasia.  The  slight  shortening  of  the  legs  produces  a 
corresponding  lessening  in  stature  but  it  is  much  less  marked  than  in 
achondroplasia,  the  central  point  of  the  body  being  only  from  one  to  two 
inches  above  the  symphysis.  Well  marked  dwarfism  as  seen  so  commonly 
in  the  latter  disease  does  not  occur  in  multiple  exostoses.  Bessel-Hagen^ 
designates  the  shortening  of  stature  as  partial  dwarfism  in  contrast  to 
the  marked  dwarfism  seen  in  achondroplasia.  With  but  few  exceptions 
the  length  growth  in  the  individual  bones  is  nearly  normal,  the  retardation 
being  confined  largely  to  the  development  in  size  and  particularly  the 
metaphyseal  part.  The  deformities  are  more  regularly  symmetrical  than 
is  the  arrangement  of  the  exostoses  and  enchondromata.  A  very  noticeable 
shortening  of  the  fibula  often  occurs  and  may  be  so  great  as  to  disturb 
its  relation  to  the  ankle  joint,  thus  producing  the  deformity  pes  valgus, 
or  rarely  pes  varus.  Knock  knees  are  seen  with  equal  frequency.  Striking 
grow^th  changes  in  the  upper  portion  of  the  femur  are  characteristic  of  the 
disease.  A  complete  synostosis  between  the  fibula  and  tibia  at  either 
end  is  frequently  found  and  rarely  a  pseudarthrosis  between  the  same 
bones  (Fig.  19).  This  is  also  true  of  the  ulna  and  radius.  In  consequence  of 
the  shortening  of  the  ulna  this  bone  may  not  articulate  with  the  carpus  but 
form  a  false  articulation  with  the  radius  in  its  lower  third  or  become  firmly 
united  with  it.  The  hand  is  then  deviated  'to  the  ulnar  side  (Fig.  20).  A 
peculiarly  characteristic  deformity  in  the  ulna  is  a  pointed  distal  end, 
the  so-called  arrowhead  form  (Fig.  20).  These  changes  in  the  ulna  are 
accompanied  by  constant  deformities  in  the  radius  which  as  a  result  of 
the  shortening  of  the  former  becomes  bowed  or  less  frequently  dislocated 
at  its  upper  end.  A  rosary  is  often  present  and  Ehrenfried^  has  observed 
a  caving  in  of  the  chest  wall.  The  spine  seldom  shows  other  deform- 
ities than  a  slight  scoliosis.  The  carpal  and  metacarpal  bones  less  fre- 
quently show  variations  in  length,  size  and  outer  form  as  also  do  the 
corresponding  bones  of  the  feet.  Analogous  changes  take  place  in  the 
pelvis  and  scapulae,  the  acromion  process  of  the  latter  being  dispropor- 
tionately large  and  the  glenoid  fossa  small.  Cystic  degeneration  is  by 
no   means  rare   and   actual   necrosis  probably  takes  place  but  is  unusual. 


Fig.  19.— Hereditary  deforming  chondrodysplasia.  Male,  age  19  years,  ^-ray  of  lower 
leg  showing  large  exostosis  at  upper  end  of  fibula  and  synostosis  between  fibula  and 
tibia  in  their  lower  portion.      (Case  of  Dr.  A.  Ehrenfried.) 


A.    Facing  490 


Fig.  20. — Hereditary  deforming  chondrodysplasia.  Male,  age  20  years.  X-ray  of  fore- 
arm and  hand,  showing  shortening  of  ulna  with  characteristic  deformity  of  distal  endand 
bowing  of  the  radius.     Note  the  ulna  deviation  of  the  hand.     (Case  of  Dr.  A.  Ehrenfried.) 


B.     Facing  490 


SYMPTOMS  491 

While  the  joint  tissues  are  not  directly  involved,  many  of  the  articula- 
tions show  distortions  or,  in  consequence  of  the  presence  of  the  exostoses 
in  the  adjacent  bones,  limitation  of  motion  is  present.  Disturbed  func- 
tions of  such  a  mechanical  nature  are  particularly  prone  to  occur  in  the 
ankle,  knee,  hip,  elbow  and  wrist. 


Metabolism 

Krieble  and  Bergeim"  studied  the  nitrogen,  sulphur,  calcium,  magnesium 
and  phosphorus  metabolism  in  a  girl  of  fifteen  suffering  from  multiple 
cartilaginous  exostoses.  The  most  striking  abnormality  found  was  a  loss 
of  twenty-one  and  eight-tenths  per  cent,  of  the  nitrogen  ingested.  The 
authors  suggest  that  the  loss  of  nitrogen  and  decrease  in  weight  were  prob- 
ably due  to  a  severe  gastrointestinal  disturbance  with  diarrhea  from  which 
the  patient  suffered.  In  spite  of  the  negative  protein  balance  the  subject 
gave  a  positive  sulphur  balance.  The  retention  of  sulphur  is  probably  to 
be  explained  as  due  to  the  extensive  cartilage  formation  which  is  a  tissue 
rich  in  sulphur.  There  was  a  retention  of  calcium,  magnesium  and  phos- 
phorus although  the  excretion  of  these  substances  in  the  urine  was  normal. 

Underbill,  Honeij  and  Bogert^^  have  very  recently  investigated  the 
calcium  and  magnesium  metabolism  in  two  cases  representing  respectively 
the  stabilized  and  progressive  stage  of  the  disease.  In  the  former  stage  the 
calcium  exchange  was  normal  and  the  magnesium  excretion  two  or  three 
times  the  normal  when  the  patient  was  on  a  diet  either  rich  or  poor  in 
these  elements.  In  the  progressive  stage  the  calcium  metabolism  was 
essentially  normal  irrespective  of  the  amount  of  calcium  in  the  diet.  The 
ratio  of  elimination  by  the  urine  and  feces  was  also  normal.  The  excretion 
of  magnesium  in  the  progressive  stage  resembled  that  of  the  stabilized 
stage  but  the  percentage  of  elimination  was  somewhat  less. 


Symptoms  and  Clinical  Characteristics 

The  disease  shows  no  primary  symptoms  and  even  the  marked  skeletal 
deformities  seen  in  the  severest  types  of  cases  give  but  few  secondary  symp- 
toms. Such  symptoms  as  do  occur  are  largely  the  result  of  complications 
arising  from  the  tumors  and  distortion  of  the  long  bones.  Pain  and  tender- 
ness over  the  tumors  are  never  present  except  as  a  result  of  secondary 
changes  such  as  ulceration,  or  inflammatory  complications.  There  are  no 
constitutional  manifestations  of  the  disease  6r  changes  in  the  blood  and 
excretions.     In  consequence  of  the  absence  of  symptoms  and  the  latency 


492  HEREDITARY  CHONDRODYSPLASIA 

of  the  process  the  presence  of  the  disease  is  seldom  recognized  until  late  in 
its  course.  The  patient  rarely  consults  the  physician  except  for  some  com- 
plication. 

In  contrast  to  the  paucity  of  symptoms  the  objective  signs  are  usually 
prominent  and  occasionally  striking.  The  bony  outgrowths  are  very 
apparent  and  may  present  quite  extraordinary  appearances.  The  deficient 
growth  of  the  fibula  with  relative  overgrowth  of  the  tibia  often  leads  to  the 
development  of  pes  valgus  and  a  similar  growth  anomaly  on  the  part  of  the 
radius  and  ulna  to  marked  deformity  of  the  wrist  with  ulna  deviation  (Fig.  20). 
As  a  result  of  such  deformities  the  posture  is  abnormal.  Mechanical  limita- 
tions in  the  joints,  particularly  the  wrists,  elbows,  hips,  knees  and  ankles, 
are  frequent  and  sometimes  very  marked.  Bessel-Hagen^  Perrin^"^,  and 
Ehrenfried^  have  emphasized  the  constancy  of  a  slight  to  moderate  diminu- 
tion in  height  which  is  chiefly  confined  to  the  lower  extremities.  The  central 
point  of  the  body  is  therefore  raised  as  in  achondroplasia  but  to  a  much  less 
degree.  The  central  point  is  never  more  than  one  or  two  inches  above  the 
symphysis. 

By  roentgenographic  examination  the  tumors  and  bone  deformities 
described  under  pathology  can  be  readily  demonstrated.  The  appearances 
in  the  tumor  growths  are  extremely  variable  depending  on  the  amount  of 
osseous  tissue  present.  Some  are  extremely  dense  and  others  very  trans- 
parent. Honeij^  has  made  a  special  study  of  the  skeleton  in  several  cases 
by  this  method  and  finds  evidence  of  a  rather  general  but  not  constant 
change  in  structure  in  the  bones  showing  exostoses  and  marked  deformity. 
In  a  few  bones  the  density  of  the  shaft  is  increased  but  a  more  common  and 
characteristic  abnormality  is  an  increased  transparency  and  longitudinal 
penciling  of  the  shaft. 

Complications 

By  reason  of  their  rarity  complications  are  of  minor  Importance.  The 
most  serious  complication  is  the  development  of  malignant  osteochondro- 
mata  which  occurs  in  a  very  small  percentage  of  cases.  Fractures  secondary 
to  trauma  and  spontaneous  fracture  of  an  exostosis  have  been  noted  In  a 
few  instances.  Ehrenfried^  collected  eight  cases  with  erosion  of  a  blood 
vessel  by  an  exostosis  and  resulting  aneurysm.  Pressure  on  nerve  trunks 
can  cause  neuralgia  or  paralysis  and  compression  signs  in  the  cord  may  be 
caused  by  Intraspinal  exostoses.  The  pelvic  deformities  have  been  known 
to  interfere  with  childbirth.  Unusual  complications  such  as  pressure 
abscess,  epilepsy,  apoplexy,  and  defective  hearing  are  sometimes  men- 
tioned. 


TREATMENT  493 


Course  and  Prognosis 

The  exostoses  show  a  more  or  less  regular  development  throughout  the 
period  of  skeletal  growth,  ceasing  with  skeletal  maturity.  A  few  authentic 
cases  have  been  collected  by  Ehrenfried^  in  which  growth  continued  in  thie 
exostoses  for  considerable  periods  after  the  age  at  which  bone  growth  ceases. 
When  growth  stops  the  exostoses  and  the  deformities  as  a  rule  become  fixed 
but  a  considerable  degree  of  retrogression  is  possible.  The  general  health 
of  the  individual  with  chondrodysplasia  is  not  impaired  and  the  occasional 
complications  are  seldom  dangerous  to  life. 


Diagnosis 

The  special  features  important  in  diagnosis  are,  (i)  multiple  cartil- 
aginous exostoses  showing  for  the  most  part  a  juxto-epiphyseal  position,  (2) 
evidences  of  slight  growth  retardation  in  the  bones  and  (3)  the  X-ray  charac- 
teristics, especially  those  about  the  knee  and  wrist,  described  above. 

The  typical  case  bears  no  real  resemblance  to  any  other  disease.  The 
congenital  origin,  the  changes  in  the  intermediary  cartilage  and  the  dwarfism 
which  are  common  to  both  achondroplasia  and  chondrodysplasia  suggest 
some  relationship  between  the  two  diseases.  This  seems  hardly  probable, 
however,  as  clinically  they  are  two  entirely  distinct  diseases  with  no  com- 
mon deformities  except  for  the  slight  tendency  to  inhibition  in  bone  growth 
in  multiple  cartilaginous  exostoses  which  simulates  the  mildest  forms  of 
dwarfism  seen  in  achondroplasia. 


Treatment 

Orthopedic  measures  may  give  relief  in  certain  cases  with  pressure 
symptoms.  Surgical  removal  of  the  bony  growths  pressing  on  nerve  trunks 
or  interfering  with  joint  function  has  frequently  been  done  with  excellent 
results.  Every  effort  should  be  made  to  build  up  the  general  vitality  of  the 
patient.    No  drug  has  any  effect  on  the  disease. 


494  DISEASES  OF  THE  BONES 

BIBLIOGRAPHY 

Part  I 

OSTEITIS  DEFORMANS  (FACET'S  DISEASE) 

1.  ARCANGELI:   Rev.  prat,  d'obst.  et  de  gynec,  Far.,  1910,  No.  7,  203. 

2.  ASKANAZY,  M.:    Arb.  a.  d.  Geb.  d.  path.  Anat Inst,   zu   Tubing, 

Brnschwg.,  1904,  IV,  398. 

3.  AUFFRET,  E.:   Rev.  d'orthop..  Far.,  1905,  2  s.,  VI,  519. 

4.  BARTLETT,  C.  J.:  Yale  M.  Jour.,  N.  Haven,  1909-10,  XVI,  367. 

5.  BECLERE,  M.  A.:   Bull,  et  mem.  Soc.  med.  d.  hop,  de  Far.,  1901,  XVIII,  929. 

6.  BOWLBY,  A.  A.:   Extract  in  Illust.  Med.  News,  1888,  II,  89. 

7.  CHASTEL:   Contribution  a  I'etude  de  I'osteite  deformante  de  Faget.    These  de 

Paris,  19 10. 

8.  CZERNY,  v.:  Wien  med.  Wchnschr.,  1873,  XXIII,  896. 

9.  DACOSTA,  J.  C,  FUNK,  E.  H.,  BERCEIM,  O.,  and  HAWK,  P.  B.:  Froc.  Am. 

Soc.  Biol.  Chemists,  Bait.,  1914,  XVII,  No.  2,  xxx. 

10.  DIEULAFOY,  G.:   Clin.  med.  de  I'Hotel-Dieu  de  Par.,  1901-02,  IV,  346. 

11.  ELTING,  A.  W.:  Johns  Hopkins  Hosp.  Bull.,  Bait.,  1901,  XII,  343. 

12.  FOURNIER:  Ann.  de  chir.  et  d'orthop..  Far.,  1903,  XVI,  115  and  132. 

13.  FR£CH0N,  J.:    Des  rapports  de  I'heredo-syphilis  osseuse  tardive  (type  Lanne- 

longue)  avec  I'osteite  deformante  progressive  (type  Faget).    These  de  Paris 
1903. 

14.  GILLES  DE  LA  TOURETTE  and  MAGDALAINE,  L.:   N.  iconog.  de  la  Salpe- 

triere,  Far.,  1894,  VII,  I. 

15.  GILLES  DE  LA  TOURETTE  and  MARINESCO:    Bull,  et  mem.  Soc.  med.  d. 

hop.  de  Par.,  1894,  3  s.,  XI,  422. 

16.  GILLES  DE  LA  TOURETTE  and  MARINESCO:   N.    conog.de   la   Salpetriere, 

Par.,  1895,  3  s.,  XII,  789. 

17.  GILLES  DE  LA  TOURETTE  and  MARINESCO:   Bull,   et   mem.  Soc.  med.  d. 

•  h6p.  de  Par.,  1895,  3  s.,  XII,  789. 

18.  GLAESSNER,  K.:  Wien.  klin.  Wchnschr.,  1908,  XXI,  1327. 

19.  GRUNER,  O.  C,  SCRIMGER,  F.  A.  C,  and  FOSTER,  L.  S.:  Arch.  Int.  Med., 

Chicago,  1912,  IX,  641. 

20.  HIGBEE,  W.  S.,  and  ELLIS,  A.  G.:  Jour.  M.  Research,  Bost.,  191 1,  XXIV,  43. 

21.  HUCHARD  and  BINET:    Bull.  Soc.  clin.  de  Far.,  1882,  VI,  8;    France  med., 

Par.,  1882,  I,  217,  230  and  247. 

22.  HUDELO,  L.,  and  HEITZ,  J.:  N.  iconog^  de  la  Salpgtriere,  Par.,  1901,  XIV,  415. 

23.  HURWITZ,  S.  H.:  Johns  Hopkins  Hosp.  Bull.,  Bait.,  1913,  XXIV,  263. 

24.  HURWITZ,  S.  H.:  Am.  Jour.  M.  Sc,  Fhila.,  1914,  CXLVII,  855. 

25.  HUTCHINSON,  J.:   Illust.  Med.  News,  1889,  II,  169. 

26.  HUTCHINSON,  J.:   Med.  Press  &  Circ,  Lond.,  1890,  n.  s.,  I,  461  and  487. 

27.  JONCHERAY,  A. :  De  I'osteite  deformante  (maladie  osseuse  de  Faget).    These  de 

Paris,  1893. 


BIBLIOGRAPHY  495 

28.  KATHOLICKY:    Wien.  klin.  Wchnschr.,  1905,  XVIII,  619  and  648. 

29.  KLIPPEL  and  WEIL,  P.:    N.  iconog.  de  la  Salpetriere,  Par.,  1909,  XXII,  i. 

30.  KLIPPEL  and  WEIL,  P.:    Rev.  neurol,  Par.,  1908,  XVI,  1243. 

31.  V.  KUTSCHA:    Wien.  klin.  Rundschau,  1906,  XIX,  1461;   Mitt.  d.  Gessellsch.  f. 

inn.  Med.  u.  Kinderh.  in  Wien,  1906,  V,  127. 

32.  LANCEREAUX:    Traite  d'anatomie  pathologique,  1885,  III,  49. 

33.  LANNELONGUE,  M.:    Bull.  Acad,  de  med..  Par.,  1903,  3  s.,  XLIX,  299;  Arch. 

gen.  de  med.,  Par.,  1903,  I,  631;  Ann.  de  chir.  et  d'orthop.,  Par.,  1903,  XVI, 
103. 

34.  LEGROS,  G.,  and  LERI,  A.:    N.  iconog.  de  la  Salpetriere,  Par.,  1909,  XXII,  24. 

35.  LERI,  A.,  and  CHATELIN:    Rev.  neurol..  Par.,  1913,  XXI,  572. 

36.  LEVI,  L.:    Bull.  Soc.  anat.  de  Par.,  1896,  LXXI,  No.  13,  439. 

37.  LEVI,  L.:    N.  iconog.  de  la  Salpetriere,  Par.,  1897,  X,  113. 

38.  LEVI,  L.:    Compt.  rend.  Soc.  de  biol.,  Par.,  1897,  10  s.,  IV,  272. 

39.  LEWALD,  L.:    Tr.  Mississippi  Valley  M.  Ass.,  1917,  XXIV,  28. 

40.  LUNN,  J.  R.:    St.  Thomas's  Hosp.  Rep;,  1883,  Lond.,'1884,  n.s.,  XIII,  43. 

41.  LYONS,  R.:    Interstate  M.  Jour.,  St.  Louis,  1912,  XIX,  2i." 

42.  MacCALLUM,  W.  G.,  and  VOEGTLIN,  C.:  Jour.  Exper.  M.,  N.  Y.,  1909,  XI, 

118. 

43.  MARIE,  P.:    Rev.  de  med.,  Par.,  1886,  VI,  297. 

44.  MARIE,  P.,  LERI,  A.,  and  CHATELIN :  Bull,  et  mem.  Soc.  med.  d.  hop.  de  Par., 

1912,  3  s.,  XXXIV,  89. 

45.  MENETRIER  and  GAUCKLER:  Bull,  et  mem.  Soc.  med.  d.  hop.  de  Par.,  1903, 

3  s.,  XX,  574;   Rev.  frang.  de  med.  et  de  chir..  Par.,  1903,  No.  40. 

46.  MOIZARD  and  BOURGES:    Arch,  de  med.  exper.  et  d'anat.  path..  Par.,  1892, 

IV,  479. 

47.  MOQUOT  and  MONTIER:    N.  iconog.  de  la  Salpetriere,  Par.,  1905,  XVIII,  61. 

48.  NEGELLEN:     De  I'osteite  deformante  (maladie  osseuse  de  Paget).     These  de 

Paris,  1903. 

49.  PACKARD,  STEELE,  and  KIRKBRIDE:    Am.  Jour.  M.  Sc,  Phila.,   1901, 

CXXII,  559. 

50.  PAGET,  J.:    Med.-Chir.  Tr.,  Lond.,  1877,  LX,  37. 

51.  PAGET,  J.:    Med.-Chir.  Tr.,  Lond.,  1882,  LXV,  225. 

52.  PAGET,  J.:    lUust.  Med.  News,  1889,  II,  181. 

53.  PEARCE,  F.  S.:    Tr.  Path.  Soc.  Phila.,  1895-97,  XVIII,  22. 

54.  PECKHAM,  F.  E.:    Am.  Jour.  Orthop.  Surg.,  Bost.,  1903-04,  I,  130;    Therap. 

Gaz.,  Detroit,  1903,  3  s.,  XIX,  577. 

55.  PESCAROLO,  B.,  and  BERTOLOTTI,  M.:    N.  iconog.  de  la  Salpetriere,  Par., 

1909,  XXII,  253. 

56.  PIC,  A.:    Rev.  d'orthop..  Par.,  1897,  VIII,  164. 

57.  PRINCE,  M.:    Am.  Jour.  M.  Sc,  Phila..  1902,  n.  s.  CXXIV,  796;   Tr.  Ass.  Am. 

Physicians,  1902,  XVII,  382. 

58.  v.  RECKLINGHAUSEN:    Abteil.  f.  Allg.  Path.  u.  Path.  Anat.,  1886. 

59.  V.  RECKLINHAUSEN:    Festschrift  der  Assistenten  f.  R.  Virchow,  1891. 

60.  REGNAULT,  F.:    Bull,  et  mem.  Soc.  anat.  de  Par.,  1914,  LXXIX,  117. 


496  DISEASES  OF  THE  BONES 

6i.  RICHARD,  P. :    Contribution  a  I'etude  de  la  maladie  osseuse  de  Paget.    These  de 
Paris,  1887. 

62.  ROBIX,  A.:    N.  inconog.  de  la  Salpetriere,  Par.,  1894,  VII,  15. 

63.  RULLIER:    Bull.  Fac.  de  med.  de  Par.,  1809,  VI,  94. 

64.  SAUCEROTTE:    Melanges  de  chin,  180 1. 

65.  SCHIFF:    Compt.  rend.  Acad.  d.  sc,  Par.,  1854,  XXXVIII,  1050. 

66.  SCHLESIXGER,  H. :    Mitt.  d.  Gessellsch.  f.  inn.  Med.  u.  Kinderh.  in  Wien,  1907, 

VI,  61;   and  1908,  VII,  loi. 

67.  SCHMIEDEX,  v.:    Deutsche  Ztschr.  f.  Chin,  Leipz.,  1903,  LXX,  207. 
SCHMIEDEN:    Deutsche  med.  Wchnschr.,  Berl.  &  Leipz.,  1903,   XXIX,  367. 

68.  SMITH,  S.  M.:    Tn  M.  Soc.  Lond.,  1905,  XXVIII,  224. 

69.  SOXXEXBERG,  W. :     Fortschr.  a.  d.  Geb.  d.  Rontgenstrahlen,  Hamb.,  1905; 

VIII,  420. 

70.  SOUQUES,  B.,  and  VALLERY-RADOT,  P. :    Bull,  et  mem.  Soc.  med.  d.  hop.  de 

Pan,  19 1 3,  3  s.,  XXXV,  206. 

71.  STILLING,  H.:    Arch.  f.  path.  Anat.  (etc.),  Berl.,  1890,  CXIX,  542. 

72.  VERGNE,  J.:    Ann.  d'ocul.,  1908,  CXL,  321. 

73.  WOLLENBERG:    Ztschr.  f.  orthop.  Chir.,  Stuttg.,  1904,  XIII,  49. 

74.  WEBER,  F.  P. :    Brit.  Joun  Child.  Dis.,  Lond.,  1908,  V,  83. 

75.  WILKS:    Tn  Path.  Soc.  Lond.,  1869,  XX,  273. 

76.  WRANY:    Vrtljschr.  f.  prakt.  Heilk.,  1867,  I,  79. 


Part  II 
SECONDARY  HYPERTROPHIC  OSTEOARTHROPATHY 

1.  ALAMARTINE,  H.:    Rev.  de  chin.  Pan,  1907,  XXXV,  992. 

2.  ALEXANDER,  J.  F.:    St.  Barth.  Hosp.  Rep.,  Lond.,  1906,  XLII,  41. 

3.  VON  BAMBERGER,  E.:    Wien.  klin.  Wchnschn,  1889,  II,  226. 

4.  VON  BAMBERGER,  E.:    Ztschn  f.  klin.  Med.,  Berl.,  1891,  XVIII,  193. 

5.  BEZANCON,  F.,  and  de  JONG,  S.  I.:  Arch.  gen.  de  med..  Pan,  1904,  II,  3100. 

6.  BROOKS,  H.:    N.  York  M.  Joun  (etc.),  1913,  XCVIII,  608. 

7.  COMBY:    Traite  des  maladies  de  I'enfance,  1898,  V,  382. 

8.  EBSTEIN,  E.:    Deutsches  Arch.  f.  klin.  Med.,  Leipz.,  1906,  LXXXIX,  67. 

9.  EMERSON,  C.  P.:    Wm.  Osier,  Modern  Medicine,  1909,  VI,  704. 

10.  GENCVA,  X.:    These  de  Montpellier,  1900. 

11.  GERAUD,  E.:    These  de  Toulouse,  1898,  No.  246. 

12.  GERHARDT,  C:    Berl.  klin.  Wchnschr.,  i«90,  XXVII,  1183. 

13.  GESSLER,  H.:     Med.  Cor.-Bl.  d.  Wiirttemb.  arztl.  Landesver.,  Stuttg.,  1893, 

LXIII,  121;   Neurol.  Centralbl.,  Leipz.,  1893,  XII,  825. 

14.  GUfiRIN,  G.,  and  ETIENNE,  G.:    Arch,  de  med.  exper.  et  d'anat.  path.,  Pan, 

1896,  VIII,  468. 

15.  GODLEE,  R.  J.:    Brit.  M.  Jour.,  Lond.,  1896,  II,  57,  116  and  1417. 

16.  GOULDESBROUGH,  C:    Arch.  Roentg.  Ray,  Lond.,  1913,  XVIII,  208. 


BIBLIOGRAPHY 


497 


17.  JANEWAY,  T.  C:    Am.  Jour.  M.  Sc,  Phila.,  1903,  CXXVI,  563. 

18.  KESSEL,  L.:    Arch.  Int.  Med.,  Chicago,  1917,  XIX,  239. 

19.  KRUGER:    Virchow's  Arch.  f.  path.  Anat.  (etc.),  Berl.,  1906,  CLXXXV,  43; 

Deutsche  med.  Wchnschr.,  Berl.  &  Leipz.,  1905,  XXXI,  1583. 

20.  LABRIT,  J.:    These  de  Bordeau,  1899. 

21.  LANDIS,  H.  R.  M.:    Penn.  M.  Jour.,  1906-07,  X,  852. 

22.  LEFEBVRE,  A.:    These  de  Paris,  1891,  No.  130. 

23.  LEMERCIER,  M.:    These  de  Paris,  1902,  No.  503. 

24.  LOCKE,  A.  E.:    Arch.  Int.  Med.,  Chicago,  1915,  XV,  659. 

25.  MARIE,  P.:    Rev.  de  med.,  Par.,  1890,  X,  i. 

26.  MASSALONGO,  R.:    PoHchn.,  Roma,  1897,  IV,  512 

27.  MOBIUS,  P.  J.:    Munchen.  med.  Wchnschr.,  1892,  XXXIX,  399. 

28.  POSTMANTIR,  S.:    Spitalul  Bucuresci,  1894,  XIV,  8. 

29.  RAUZIER,  G.:    Rev.  de  med..  Par.,  1891,  XI,  30. 

30.  RENDU  and  BOULLOCHE,  P. :    Bull,  et  mem.  Soc.  med.  d.  h6p.  de  Par.,  1901 ,  3 

s.,  XVIII,  127. 

31.  REYNAUD,  G.,  and  AUDIBERT,  V.:    Arch.  prov.  de  chin.  Par.,  1901,  X,  35. 

32.  SCHMIDT,  H.:     Munchen.  med.  Wchnschr.,  1892,  XXXIX,  633;     Schmidt's 

Jahrb.,  1891,  CCXXX,  270. 

33.  STERNBERG,  M.:    Nothnagel's  spez.  Path.  u.  Therap.,  1903,  VII,  Part  11,  72. 

34.  TELEKY:    Wien.  klin.  Wchnschr.,  1897,  X,  143. 

35.  THAYER,  W.  S.:    N.  York  M.  Jour,  (etc.),  1896,  LXIII,  33.    Phila.  M.  Jour., 

1898,  II,  955. 

36.  THOMPSON,  H.  E.  S.:  Tr.  Med.-Chir.  Soc.  Lond.,  1904,  LXXXVII,  85. 

37.  THORBURN,  W.:    Brit.  M.  Jour.,  Lond.,  1893,  I,  1155. 

38.  VEDEL,  v.:    Presse  med.,  Par.,  1896,  IV,  697. 

39.  VILLARD,  H.:    N.  Montpel.  med.,  1894,  III,  509  and  532. 

40.  WALTERS,  F.  R.:    St.  Thomas's  Hosp.  Rep.,  Lond.,  1895,  n.  s.,  XXIV,  i. 

41.  WYNN,  W.  H.:    Birmingham  Med.  Rev.,  1904,  LV,  139,  156,  212  and  282. 


Part  III 
OSTITIS  FIBROSA  CYSTICA 

1.  VON  BERGMANN,  G.:    Deutsch.  Zeitschr.  f.  Chin,  1913,  CXXIV,  i. 

2.  BLOODGOOD,  J.  C:    Trans.  Am.  Surg.  Assoc,  1910,  XXVIII,  116. 

3.  BOLOGNESI,  J.:    Deutsch.  Zeitschn  f.  Chin,  1914,  CXXXI,  382. 

4.  BOOKMAN,  A.:    Med.  Rec,  N.  Y.,  1915,  LXXXVII,  539. 

5.  VON  BRUNN,  M.:    Beitn  z.  klin.  Chin,  1906,  L,  70. 

6.  VON  BRUNN,  M.:    Beitr.  z.  klin.  Chir.,  1905,  XLV,  H.  2,  344. 

7.  FRANGENHEIM,  F.:    Beitn  z.  klin.  Chin,  1912,  LXXVI,  227. 

8.  FRANKE,  F.:    Verhandl.  d.  deutsch.  Gesellsch.  f.  Chir.,  1899,  123;  Arch.  L  klin. 

Chir.,  1899,  LIX,  186. 

9.  FiJJII:    Deutsch.  Zeitschr.  f.  Chir.,  1912,  CXIV,  25. 

Vol.  IV.  32 


498  DISEASES  OF  THE  BONES 

0.  GAUGELE:   Fortschr.  a.  d.  Geb.  d.  Rontgen-strahlen,  1906,  IX,  317. 

1.  HARTMANN,  K.:    Beitr.  z.  klin.  Chin,  1911,  LXXIII,  627. 

2.  HEINEKE,  H.:    Beitr.  z.  klin.  Chin,  1903,  XL,  481. 

3.  HIRSCHBERG,  K.:    Ziegler's  Beitn  z.  path.  Anat.,  1889,  VI,  511. 

4.  JENCKEL:    Centralbl.  f.  Chin,  1912,  XXXIX,  350. 

5.  KONIG,  F.:    Langenbeck's  Arch.  f.  klin.  Chin,  1898,  LVI,  667. 

6.  KONJETZUY,  G.  E.:    Beitn  z.  kUn.  Chin,  1910,  LXVIII,  811. 

7.  LANDON,  L.  H.:    Ann.  Surg.,  Phila.,  1914,  LX,  570. 

8.  LISSAUER:     Monatschr.  f.  Unfallheilkunde  u.  Invalidenwesen,  1905,  XII,  51. 

9.  MATSOUKA,  M.:    Deutsch.  Zeitschn  f.  Chir.,  1909,  CII,  515. 

20.  VON  MIKULICZ:    N.  Yorker  med.  Monatschn,  1904,  XVI,  83. 

21.  VON  MIKULICZ:    Centralbl.  f.  Chin,  1904,  XXXI,  H.  2,  1323. 

22.  MONCKEBERG:    Verhandl.  d.  deutsch.  path.  Gesellsch.,  1904,  VII, 

23.  MURPHY,  J.  B.:    Clinic  J.  B.  Murphy,  Chicago,  1913,  II,  783. 

24.  PFEIFFER,  C:    Beitn  z.  klin.  Chin,  1907,  LIII,  473. 

25.  VON  RECKLINGHAUSEN,  F.  D.:    Festschr.  Rudolf  Virchow,  1891,  s.  9. 

26.  REHN,  L. :  Verhandl.  d.  deutsch.  Gesellsch.  f.  Chir.,  1904,  33  Kongress,  424. 

27.  RINGEL:    Deutsche  med.  Wchnschn,  1918,  XLIV,  367. 

28.  SAURBORN,  W.:    Virchow's  Arch.,  i9io,CCI,  467. 

29.  SILVER,  D.:    Am.  J.  Orth.  Surg.,  1911-1912,  IX,  563. 

30.  TIETZA:    Beitr.  z.  klin.  Chir.,  1907,  LII,  495. 

31.  VIRCHOW,  R.  L.  K.:    Monats-Bericht  der  Kgl.  Bed.  Akad.  der  Wissenschaften 

Mathemotphysikal  Klasse,  1876,  960. 


Part  IV 
OSTEOPSATHYROSIS  (OSTEOGENESIS  IMPERFECTA) 

1.  ADAMS,  J.  E.:    Proc.  Roy.  Soc.  Med.,  Lond.,  1918,  XII,  No.  2,  Sect.  Stud. 

Dis.  Child.,  5. 

2.  BAMBERG,  K.,  and  HULDSCHINSKY,  K.:    Jahrb.  f.  Kinderh.,  Leipz.,  1913, 

LXXVIII,  Erganzgshft.,  214. 

3.  BIGGS,  M.  H.:    Univ.  Penn.  M.  Bull.,  Phila.,  1902-03,  XV,  488. 

4.  BIRNBAUM,  R.:     A  Clinical  Manual  of  the  Malformations  and  Congenital 

Diseases  of  the  Foetus,  Trans,  by  Blacker,  London,  1912,  246. 

5.  BLAINE,  E.S.:    Am.  J.  Roentgenol.,  Detroit,  1916,  III,  438. 

6.  BOOKMAN,  A.:    Am.  J.  Dis.  Child.,  Chicago,  1914,  VII,  436. 

7.  CZERNY,  A.:     Berl.  kUn.  Wchnschn,  1919,  LVI,  310;  Deutsche  med.  Wchnschn, 

Berl.  &  Leipz.,  1919,  XLV,  259  and  389. 

8.  EDDOWES,  A.:    Brit.  M.  Joun,  Lond.,  1900,  II,  222. 

9.  FRANGENHEIM,  P.:     Die  Krankheiten  des  Knochensystems  in  Kindesalter, 

(Neue  Deutsche  Chirurgie),  Enke,  Stuttgart,  1913,  45. 

10.  FUCHS,  F.:    Virchow's  Arch.  i.  path.  Anat.  (etc.),  Berl.,  1912,  CCVII,  75. 

11.  GRIFFITH,  J.  P.  C:    Am.  Joun  M.  Sc,  Phila.,  1897,  CXIII,  426. 


BIBLIOGRAPHY  499 

12.  GURLT:   Handbuch  der  Lehre  von  den  Knochenbriichen,  I,  Berlin,  1862,  Th. 

I,  147. 

13.  HARBITZ,  F.:    Beitr.  z.  path.  Anat.  u.  z.  allg.  Path.,  Jena,  1901,  XXX,  605. 

14.  HESS,  J.  H.:   Arch.  Int.  Med.,  Chicago,  1917,  XIX,  163. 

15.  HOHLFELD,  M.:    Miinchen  med.  Wchnschr.,  1905,  LII,  303. 

16.  KIENBOCK,    R. :   Fortschr.    a.    d.    Geb.    d.    Rontgenstrahlen,    Hamb.,    191 5, 

XXIII,  122. 

17.  VON  LOBSTEIN:   Traite  d'anatomie  pathologique,  Paris  and  Strassbourg,  1829 

bis  1834,  II,  204. 

18.  LOOSER,  E.:    Mitt.  a.  d.  Grenzgeb.  d.  Med.  u.  Chin,  Jena,   1906,  XV,   161. 

19.  LOVETT,  R.  W.,  and  NICHOLS,  E.  H.:   Brit.  M.  Jour.,  Lond.,  1906,  II,  915. 

20.  MICHEL,  F.:   Virchow's  Arch.  f.  path.  Anat.  (etc.),  Berl.,  1903,  CLXXIII,  i. 

21.  MIXSELL,  H.  R.:  Arch.  Pediat.,  1917,  XXXIV,  756. 

22.  NATHAN,  P.  W.:  Am.  Jour.  M.  Sc,  Phila.,  1905.  CXXIX,  I. 

23.  NIKLAS,  F.:    Beitr.  z.  path.  Anat.  u.  z.  allg.  Path.,  Jena,  1915,  LXI,  loi. 

24.  OSTHEIMER,  M.:   Jour.  Am.  M.  Ass.,  Chicago,  1914,  LXIII,  1896. 

25.  PORAK,  C,  and  DURANTE,  G.:   N.    iconog.    de    la    Salpltriere,    Par.,   1905, 

XVIII,  507. 

26.  SCHUCHARDT:    Die  Krankheiten  der  Knochen  u.  Gelenke,  Stuttgart,   1899, 

61. 

27.  SCHWARZ,  H.,  and  BASS,  M.  H.:  Am.  Jour.  Dis.  Child.,  Chicago,  1913,  V,  131. 

28.  SEGAWA,  M.:  Ztschr.  f.  Kinderh.,  Berl.,  1915,  XII,  246. 

29.  STILLING,  H.:   Virchow's  Arch.  f.  path.  Anat.  (etc.),  Berl.,  1889,  CXV,  357. 

30.  SUMITA,  M.:    Deutsche  Ztschr.  f.  Chin,  Leipz.,  1910,  CVII,  i. 

31.  VROLIK:   Arch.  f.  Gynaek.,  Berl.,  1849,  XXX,  275. 

32.  ZIEGLER,  E. :  Lehrbuch  der  speziellen  pathologischen  Anatomie,  Jena,  1906,  162. 


Part  V 

OSTEOMALACIA 

1.  ARCANGELI,  U.:  Suppl.  al  Policlin.,  Roma,  1902,  VIII,  705;  Bull.  d.  n  Accad. 

med.  di  Roma,  1907,  XXXI H,  249. 

2.  BERNARD,  L.:  Presse  med.,  Pan,  1909,  XVII,  825. 

3.  BOSSI,  L.  M.:  Semaine  med..  Pan,  1907,  XXVII,  69  and  142. 

4.  DOCK,  G.:  Modern  Medicine  (Osier),  Phila.  &  N.  Y.,  1909,  VI,  559. 

5.  DRASCHE:  Senile  Osteomalacia,  Beitr.  z.  inn.  Med.  (Festschr.  f.  d.  Cong.  f.  in. 

Med.,  1899). 

6.  EICHORST:   Cor.-Bl.  f.  schweiz.  Aerzte,  1909,  XXXIX,  779. 

7.  FEHLING,  H.:  Arch.  f.  gynaek.,  Berl.,  1891,  XXXIX,  171. 

8.  FOCHIER,  A.:  Lyon  med.,  1879,  XXXI,  393,  473,  505  and  545. 

9.  GUTHRIE,  A.  C. :    Prescriber,  Edinb.,  1909,  III,  150. 

10.  HANAU,  A.:  Fortschn  d.  Med.,  1892,  X,  237. 

11.  HELLIER:    Lancet,  Lond.,  1895,  I,  807. 


500  DISEASES  OF  THE  BONES 

12.  HOENNICKE:    Bed.  klin.  Wchnschr.,  1904,  XLI,  1154. 

13.  McCRUDDEN,  F.  H.:  Am.  Jour.  Physiol.,  Bost.,  1906,  XVII,  32. 

14.  McCRUDDEN,  F.  H.:  Am.  Jour.  Physiol.,  Bost.,  1906,  XVII,  211. 

15.  McCRUDDEN,  F.  H.:  Arch.  Int.  Med.,  Chicago,  1910,  V,  596. 

16.  McCRUDDEN,  F.  H.:  Jour.  Biol.  Chem.,  N.  Y.,  1910,  VII,  185. 

17.  McCRUDDEN,  F.  H.:  Jour.  Biol.  Chem.,  N.  Y.,  1910,  VII.  199. 

18.  McCRUDDEN,  F.  H.:  Arch.  Int.  Med.,  Chicago,  1912,  IX,  273. 

19.  OGATA,  M.:   Beitr.  z.  Geburtsh.  u.  Gynaek.,  Leipz.,  1909,  XIV,  492. 

20.  PETRONE,  M.:   Riforma  med.,  1892,  VIII,  28. 

21.  PORRO:   Delia  amputazione  utero-ovarien  come  complemento  di  taglia  cesarea, 

Milano,  1876. 

22.  VON  RECKLINGHAUSEN,  R.:   Festschr.  Rudolf  Virchow,  Berl.,  1901. 

23.  VON  RECKLINGHAUSEN,   R. :    Untersuchungen   uber  Rhachitis  und  Osteo- 

malacic, Jena,  1910. 

24.  VON  RIBBERT,  H.:   Biblioth.  Med.,  1893,  Abt.  C,  Heft  2. 

25.  SCHIFFMACHER:  Munchen.  med.  Wchnschr.,  1904,  LI,  555. 

26.  SCHMIDT,  M.  B.:  Verhandl.  d.  deutsch.  path.  Gesellsch.,  1909,  XIII,  3. 

27.  SCOTT,  A.  C:   Indian  Jour.  M.  Research,  Calcutta,  1916-17,  IV,  140. 

28.  SCOTT,  A.  C:   Indian  Jour.  M.  Research,  Calcutta,  1916-17,  IV,  169. 

29.  TASHIRO,  Y.:  Beitr.  z.  path.  Anat.  u.  z.  allg.  Path.,  Jena,  1903,  XXXIV,  220. 

30.  ZESAS,  D.  G.:   Centralbl.  f.  d.  Grenzgeb.  d.  Med.  u.  Chir.,  Jena,  1907,  X,  801, 

849  and  881. 


Part  VI 
ACHONDROPLASIA  (CHONDRODYSTROPHIA  FOETALIS) 

1.  APERT:   Nouv.  Icon.  d.  la  Salpetr.,  1901,  XIV,  290, 

2.  BALLESTER,  F.  L.:    Rev.  de  med.  y  cirug.  pract.,  Madrid,  1914,  CV,  166. 

3.  BUSCH:    Neue  Ztschr.  f.  Geburtskunde  u.  Gynaekologie,  1836,  IV,  no. 

4.  DUFOUR,  H.:   Nouv.  Icon.  d.  la  Salpetr.,  1906,  XIX,  133. 

5.  DURANTE,  G. :    Rev.  med.  de  la  Suisse  Rom.,  Geneve,  1902,  XXII,  809. 

6.  EBERT:   Festschrift,  Leipzig,  1878. 

7.  EMERSON,  C.  P.:   Modern  Medicine,  (Osier  and  McCrae)  Lea  &  Febiger, 

1909,  VI,  683. 

8.  FRANGENHEIM,  P.:   Neue  Deutsche  Chir.,  1913,  X,  13. 

9.  FUSSELL,  M.  H.,  and  PANCOAST,  H.  K.:  Penn.  M.  Jour.,  1909-10,  XIII,  751. 

10.  GRAWITZ,  P.:   Virchow's  Arch.  f.  path.  Anat.  (etc.),  Berl.,  1885,  C,  256. 

11.  JANSEN,  M.:   Achondroplasia:    Its  Nature  and  its  Cause.     Brill,  Leiden,  1912. 

12.  KASSOWITZ,  M.:   Wien.  med.  Wchnschr.,  1902,  LII,  1358,  1410  and  1451. 

13.  KAUFMANN,   E.:    Berlin,    1892;    Beitr.  z.  path.  Anat.  u.   z.   allg.  Path.,   Jena, 

1893,  XIII,  33. 

14.  KIRCHBERG,  A.,  and  MARCHAND,  F.:  Beitr.  z.  path.  Anat.  u.  z.  allg.  Path., 

^   Jena,  1889,  V,  183. 


BIBLIOGRAPHY  501 

15.  MacCALLUM,  W.  G.:   Johns  Hopkins  Hospital  Bull.,  1915,  XXVI,  182.    Proc. 

N.  York  Path.  Soc,  1914-1915,  n.  s.,  XIV,  139. 

16.  MARIE,  P.:   Presse  med.,  Par.,  1900,  VIII,  17. 

17.  MULLER,  H.:   Wiirzb.  med.  Ztschr.,  i860,  I,  221. 

18.  OPIE,  E.  L.,  and  ALLISON,  N.:  Jour.  Med.  Research,  Post,  1917,  XXXVI,  277. 

19.  PARHON,  C,  SHUNDA,  A.,  and  ZALPLACHTA,  J.:  Nouv.  Icon.  d.  la  Salpetr., 

1905,  XVIII,  539- 

20.  PARROT:   Bull.  Soc.  d 'anthrop.  de  Par.,  1878,  III,  296. 

21.  PORAK,  C:  Nouvel.  arch,  d'obst.  et  de  gyn.,  1889,  IV,  551. 

22.  PORAK,  C,  and  DURANTE,  G.:  Nouv.  Icon.  d.  la  Salpetr.,  1905,  XVIII,  481. 

23.  PORTER,  J.  H.:  Brit.  M.  Jour.,  Lond.,  1907,  I,  12. 

24.  RANKIN,  G.,  and  MACKAY,  E.  C.:    Brit.  M.  Jour.,  Lord.,  1906,  I,  1518. 

25.  REGNAULT,  F.:  Arch.  gen.  de  med..  Par.,  1902,  9  s.,  VII,  232. 

26.  ROMBERG,  E. :    Dissertatio  Inauguratis  de  Rachitide  Congenita,  Berlin,  1817. 

27.  SCHIDLOWSKY,  E.:    Inaug.   Dissertation,  Bedin,  1885. 

28.  SOMMERING,  S.  T.:   Abbildungen  u.  Beschreibungen  einiger  Misgeburten  u. 

s.  w..  Table  XI,  Mains,  1791. 

29.  SYMINGTON,  J.:   Rep.  Lab.  Roy.  Coll.  Phys.,  1892,  IV,  237. 

30.  SYMMERS,  D.,  and  WALLACE,  G.  H.:  Arch.  Int.  Med.,  Chicago,  1913,  XII,  37. 

31.  URTEL,  H.  P.:    Inaug.  Dissertation,  Halle,  1873. 

32.  VARIOT,  G. :   Bull.  Soc.  de  pediat.  de  Par.,  1903,  V,  150  and  173. 

33.  VIRCHOW,  R.:    Quoted  by  Kaufmann  in;    Ges.-Abhandl.  z.  wissensch.  Med., 

Frankfurt,  1856,  975. 

34.  WEBER,  M.  J.:   Jour.  t.  Geburtsh.  Frauenzim.  u.  Kinderkr.,  1830,  IX,  292. 

35.  WHEELDON,T.  F.:   Am.  Jour.  Dis.  Child.,  Chicago,  1920,  XIX,  i. 

36.  WINKLER:   Arch.  f.  Gynaek.,  Berl.,  1871,  II,  loi. 


Part  VII 

HEREDITARY  DEFORMING  CHONDRODYSPLASIA 
(MULTIPLE  CARTILAGINOUS  EXOSTOSES) 

1.  ASHHURST,  A.  P.  C:   Ann.  Surg.,  1916,  Phila.,  LXIII,  167. 

2.  BESSEL-HAGEN:   Arch,  f.  klin.  Chir.,  Berl.,  1890,  XLI,  420,  505  and  749. 

3.  VON  BERGMANN,  E.:   St.  Petersb.  med.  Wchnschr.,  1876,  i. 

4.  EHRENFRIED,  A.:   Jour.  Am.  M.  Ass.,  Chicago,  1915,  LXIV,  1642. 

5.  EHRENFRIED,  A.:   Jour.  Am.  M.  Ass.,  Chicago,  1917,  LXVIII,  502. 

6.  EHRENFRIED,  A.:  Am.  J.  Orthop.  Surg.,  Boston,  1917,  XV,  463. 

7.  FRANGENHEIM,  P.:   Ergebn.  d.  Chir.  u.  Orth.,  Berl,  1912,  IV,  170. 

8.  GIBNEY,  V.  P.:   Med.  Rec,  N.  Y.,  1875,  X,  300. 

9.  HONEIJ,  J.  A.:   Arch.  Int.  Med.,  Chicago,  1920,  XXV,  584. 
ID.  KEITH,  A.:   Jour.  Am.  M.  Ass.,  Chicago,  1920,  LXXIV,  539. 

II.   KRIEBLE,  V.  K.,  and  BERGEIM,  O.:  J.  Biol.  Chem.,  N.  Y.,  1919,  XXXVII, 
179. 


r//^f  «) 


502  DISEASES  OF  THE  BONES 

12.  LENORMANT,  C. :   Rev.  d'orth.,  1905,  Par.,  VI,  193. 

13.  PERCY,  N.  M.:  Surg.,  Gynec.  and  Obst,  Chicago,  1915,  XX,  619. 

14.  PERRIN,  M.:   Rev.  d'orth..  Par.,  1914,  V,  53. 

15.  REINECKE:   Beitr.  z.  klin.  Chin,  Tubing.,  1890,  VII,  657. 

16.  TURNER,  P.:  Proc.  Roy.  Soc.  Med.,  Lond.,  1913,  VII,  Part  i,  107. 

17.  UNDERHILL,  F.  P.,  HONEIJ,  F.A.,  and  BOGERT,  L.  J.:  J.  Exper.  M.,  N.  Y., 

1920,  XXXII,  65. 


COLUMBIA  UNIVERSITY  LIBRARIES 

This  book  is  due  on  the  date  indicated  below,  or  at  the 

expiration  of  a  definite  period  after  the  date  of  borrowing,  as  j 
provided  by  the  rules  of  the  Library  or  by  special  arrange- 
ment with  the  Librarian  in  charge. 

DATE  BORROWED 

DATE  DUE 

DATE  BORROWED 

DATE  DUE 

■     -  '   :^;J 

«    ?*  H. 

i.      ■^.^A,"               i 

f  V"  -i        JMi 

A? Hz 

^  Z^JLi  **  / 

\Ai  1  j  mM 

} 

.V:^ 

C28(i14i)m100 

L79 


*^©  bones 

BIN? 


^ 


^^CO^LUMBIA^UW™LIBRARIES(hs,,stx) 
Diseases  of  the  bones 


2002456877 


i,'li'l'*»4 


